Octahydropyrrolopyrroles their preparation and use

ABSTRACT

The present invention provides compounds comprising variously substituted octahydropyrrolopyrroles, their synthesis, methods of making, methods of using, compositions and formulations thereof.

This application is a § 371 national stage of PCT InternationalApplication No. PCT/US2014/026699, filed Mar. 13, 2014, claiming thebenefit of U.S. Provisional Application No. 61/785,334, filed Mar. 14,2013, the contents of each of which are hereby incorporated by referencein their entirety.

The invention was made with government support under Grant numbersNS067594 and NS074476 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

Throughout this application, certain publications are referenced inparentheses. Full citations for these publications may be foundimmediately preceding the claims. The disclosures of these publicationsin their entireties are hereby incorporated by reference into thisapplication in order to describe more fully the state of the art towhich this invention relates.

BACKGROUND OF THE INVENTION

Age-related macular degeneration (AMD) is the leading cause of blindnessin developed countries. It is estimated that 62.9 million individualsworldwide have the most prevalent atrophic (dry) form of AMD; 8 millionof them are Americans. Due to increasing life expectancy and currentdemographics this number is expected to triple by 2020. There iscurrently no FDA-approved treatment for dry AMD. Given the lack oftreatment and high prevalence, development of drugs for dry AMD is ofupmost importance. Clinically, atrophic AMD represents a slowlyprogressing neurodegenerative disorder in which specialized neurons (rodand cone photoreceptors) die in the central part of the retina calledmacula (1). Histopathological and clinical imaging studies indicate thatphotoreceptor degeneration in dry AMD is triggered by abnormalities inthe retinal pigment epithelium (RPE) that lies beneath photoreceptorsand provides critical metabolic support to these light-sensing neuronalcells.

Experimental and clinical data indicate that excessive accumulation ofcytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin)in the RPE is a major trigger of dry AMD (2-9). In addition to AMD,dramatic accumulation of lipofuscin is the hallmark of Stargardt Disease(STGD), an inherited form of juvenile-onset macular degeneration. Themajor cytotoxic component of RPE lipofuscin is pyridinium bisretinoidA2E (FIG. 1). Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE,and A2-DRP-PE (40, 41). Formation of A2E and other lipofuscinbisretinoids, such as A2-DHP-PE(A2-dihydropyridine-phosphatidylethanolamine) and atRALdi-PE(all-trans-retinal dimer-phosphatidylethanolamine), begins inphotoreceptor cells in a non-enzymatic manner and can be considered as aby-product of the properly functioning visual cycle.

A2E is a product of condensation of all-trans retinaldehyde withphosphatidyl-ethanolamine which occurs in the retina in a non-enzymaticmanner and, as illustrated in FIG. 4, can be considered a by-product ofa properly functioning visual cycle (10). Light-induced isomerization of11-cis retinaldehyde to its all-trans form is the first step in asignaling cascade that mediates light perception. The visual cycle is achain of biochemical reactions that regenerate visual pigment (11-cisretinaldehyde conjugated to opsin) following exposure to light.

As cytotoxic bisretinoids are formed during the course of a normallyfunctioning visual cycle, partial pharmacological inhibition of thevisual cycle may represent a treatment strategy for dry AMD and otherdisorders characterized by excessive accumulation of lipofuscin (25-27,40, 41).

SUMMARY OF THE INVENTION

The present invention provides a compound having the structure:

wherein

R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ or C₁-C₄alkyl:

A is absent or present, and when present is

B is substituted or unsubstituted monocycle, bicycle, heteromonocycle,heterobicycle, benzyl, CO₂H or (C₁-C₄ alkyl)-CO₂H,

-   -   wherein when B is CO₂H, then A is present and is

or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1. Structure of bisretinoid A2E, a cytotoxic component of retinallipofuscin.

FIG. 2, Structure of bisretinoid atRAL di-PE (all-transretinaldimer-phosphatidyl ethanolamine), a cytotoxiccomponent of retinallipofuscin. R₁ and R₂ refer to various fatty acid constituents.

FIG. 3. Structure of bisretinoid A2-DHP-PE, a cytotoxic component ofretinal lipofuscin.

FIG. 4. Visual cycle and biosynthesis of A2E. A2E biosynthesis beginswhen a portion of all-trans-retinal escapes the visual cycle (yellowbox) and non-enzymatically reacts with phosphatidyl-ethanolamine formingthe A2E precursor, A2-PE. Uptake of serum retinol to the RPE (gray box)fuels the cycle.

FIG. 5. Three-dimensional structure of the RBP4-TTR-retinol complex.Tetrameic TTR is shown in blue, light blue, green and yellow (largeboxed region). RBP is shown in red (unboxed region) and retinol is shownin gray (small boxed region) (28).

FIG. 6. Structure of fenretinide, [N-(4-hydroxy-phenyl)retinamide,4HRP], a retinoid RBP4 antagonist.

FIG. 7. Schematic depiction of the HTRF-based assay format forcharacterization of RBP4 antagonists disrupting retinol-induced RBP4-TTRinteraction.

FIG. 8. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof compounds 17-24 and 27-39. PPB: Plasma protein binding, H: Human, M:Mouse, R: Rat, D: Dog.

FIG. 9. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof compounds 41-59.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound having the structure:

wherein

R₁, R₂, B₃, R₄, and R₅ are each independently H, halogen, CF₃ or C₁-C₄alkyl;

A is absent or present, and when present is

B is substituted or unsubstituted monocycle, bicycle, heteromonocycle,heterobicycle, benzyl, CO₂H or (C₁-C₄ alkyl)-CO₂H,

-   -   wherein when B is CO₂H, then A is present and is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound having the structure:

3 In some embodiments, the compound having the structure:

In some embodiments, the compound having the structure:

In some embodiments, the compound wherein B is a substituted orunsubstituted heterobicycle.

In some embodiments, the compound wherein B has the structure:

wherein

α, β, χ, and δ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₁ is S, O, or N;

Z₂ is S, O, N or NR₇,

-   -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane;

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

In some embodiments of the above compound, the compound wherein B hasthe structure:

wherein

when α is present, then Z₁ and Z₂ are N, X is N, β is present, and χ andδ are absent, or when α is present, then Z₁ is O or S, Z₂ is N, X is C,χ is present, and β and δ are absent;

when α is absent, then Z₁ is N, Z₂ is N—R₇, X is C, β and δ are present,and χ is absent, or when α is absent, then Z₁ is N, Z₂ is O or S, X isC, β and δ are present, and χ is absent.

8 In some embodiments, the compound wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and whenpresent each is a bond;

Z₁ is S, O or N;

Z₂ is S, O, N or N—R₇,

-   -   wherein R₇ is H, C₁-C₁₀ alkyl, or oxetane;

X is C or N;

Y₁, Y₂, Y₃, and each occurrence of Y₄ are each independently CR₈,C(R₉)₂, N—R₁₀, O, N, SO₂, or C═O,

-   -   wherein    -   R₈ is H, halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀        alkyl), C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄        alkyl), C(O)—NH(C₂-C₄ alkyl)₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH(C₁-C₁₀ alkyl), SO₂—N(C₁-C₁₀        alkyl)₂, CN, or CF₃;    -   R₉ is H or C₁-C₁₀ alkyl;    -   R₁₀ is H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃,        (C₁-C₁₀ alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl),        SO₂—(C₁-C₁₀ alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀        alkyl)-halogen, C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₁₀ alkyl)-CF₃,        C(O)—(C₁-C₁₀ alkyl)-OCH₃, C(O)—(C₁-C₁₀ alkyl)-halogen,        C(O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₁₀        alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments of the above compound, the compound wherein B hasthe structure:

wherein

when α is present, then Z₁ and Z₂ are N, X is N, β is present, and χ andδ are absent, or when α is present, then Z₁ is O or S, Z₂ is N, X is C,χ is present, and β and δ are absent;

when α is absent, then Z₁ is N, Z₂ is N—R₇, X is C, β and δ are present,and χ is absent, or when α is absent, then Z₁ is N, Z₂ is O or S, X isC, β and δ are present, and χ is absent.

when ε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃, and Y₄are independently C—R₈ or N;

when ε and ϕ are each absent, then n=0, 1 or 2, each of Y₁, Y₂, Y₃, andeach occurrence of Y₄ are independently C(R₉)₂, N—R₁₀, O, or SO₂.

10. The compound of claim 9,

-   -   wherein    -   β and δ are present;    -   α, χ, ε, and ϕ are absent;    -   Z₁ is N;    -   Z₂ is O, S, or N—R₇,        -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 0;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁ and Y₃ are each CH₂ or C(CH₃)₂; and    -   Y₂ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄ alkyl),            SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄            alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃,            C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,            C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄            alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁, Y₂ and Y₄ are each CH₂ or C(CH₃)₂; and    -   Y₃ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁, Y₃ and Y₄ are each CH₂ or C(CH₃)₂; and    -   Y₂ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 2;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁, Y₃ and each occurrence of Y₄ are each CH₂ or C(CH₃)₂; and    -   Y₂ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₂, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₂-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₂-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₂-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₀ is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, t-Bu, CH₂OCH₃, CH₂CF₃, CH₂Cl, CH₂F,CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is SO₂—CH₃, SO₂—CH₂CH₃,SO₂—CH₂CH₂CH₃, SO₂—CH(CH₃)₂, SO₂—CH₂CH(CH₃)₂, SO₂-t-Bu, SO₂—CH₂OCH₃,SO₂—CH₂CF₃, SO₂—CH₂Cl, SO₂—CH₂F, SO₂—CH₂CH₂OCH₃, SO₂—CH₂CH₂CF₃,SO₂—CH₂CH₂Cl, SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂CH₃,C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₃,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   R₇ is H, CH₃, CH₂CH₃, CH(CH₃)₂, or

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁ and Y₄ are each CH₂; and    -   Y₂ is C═O and Y₃ is N—R₁₀, or Y₃ is C═O and Y₂ is N—R₁₀,        -   wherein        -   R₁₀ is H or C₁-C₄ alkyl.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   R₇ is H, CH₃, CH₂CH₃, CH(CH₃)₂, or

and each R₁₀ is H or CH₃.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y₄ are each CH₂; and    -   one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, or        N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            C₁-C₄ alkyl)-C(O)OH, or oxetane.

In some embodiments, the compound wherein H has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y₄ are each CH₂; and    -   one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₂ is O, SO₂, or        N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₁ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF), C(O)—(C₂-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            C₁-C₄ alkyl)-C(O)OH, or oxetane.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₀ is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, t-Bu, CH₂OCH₃, CH₂CF₃, CH₂Cl, CH₂F,CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is SO₂—CH₃, SO₂—CH₂CH₃,SO₂—CH₂CH₂CH₃, SO₂—CH(CH₃)₂, SO₂—CH₂CH(CH₃)₂, SO₂-t-Bu, SO₂—CH₂OCH₃,SO₂—CH₂CF₃, SO₂—CH₂Cl, SO₂—CH₂F, SO₂—CH₂CH₂OCH₃, SO₂—CH₂CH₂CF₃,SO₂—CH₂CH₂Cl, SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂CH₃,C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₃,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein

-   -   β, δ, ε, and ϕ are present;    -   α and χ are absent;

Z₁ is N;

-   -   Z₂ is O or N—R₇,        -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N,        -   wherein each R₈ is independently H, halogen, C₁-C₄ alkyl,            C₁-C₄ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,            C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃,

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃ and Y₄ are each CH;    -   Y₁, Y₂, Y₃ are each CH and Y₄ is N;    -   Y₁, Y₂, Y₄ are each CH and Y₃ is N;    -   Y₁, Y₃, Y₄ are each CH and Y₂ is N; or    -   Y₂, Y₃, Y₄ are each CH and Y₁ is N.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   R₇ is H, CH₂CH₃, CH₃, CH(CH₃)₂, or

and

-   -   each R₈ is independently H, Cl, Br, F, OCH₃, OCH₂CH₃, CF₃, CN,        CH₃, CH₃CH₃, C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃, or        NHC(O)—N(CH₃)₂.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N,        -   wherein R₈ is H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, or CF₃,

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃ and Y₄ are each CH;    -   Y₁, Y₂, Y₃ are each CH and Y₄ is N;    -   Y₁, Y₂, Y₄ are each CH and Y₃ is N;    -   Y₁, Y₃, Y₄ are each CH and Y₂ is N; or    -   Y₂, Y₃, Y₄ are each CH and Y₁ is N.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   α and β are present;    -   χ, δ, ε, and ϕ are absent;    -   Z₁ is N;    -   Z₂ is N; and    -   X is N.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y₄ are each CH₂; and    -   one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, or    -   N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C1-C4 cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, or oxetane.

41 In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

R₁₀ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, t-Bu, CH₂OCH₃,CH₂CF₂, CH₂Cl, CH₂F, CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein

R₁₀ is SO₂—CH₃, SO₂—CH₂CH₃, SO₂—CH₂CH₂CH₃, SO₂—CH(CH₃)₂,SO₂—CH₂CH(CH₃)₂, SO₂-t-Bu, SO₂—CH₂OCH₃, SO₂—CH₂CF₃, SO₂—CH₂Cl, SO₂—CH₂F,SO₂—CH₂CH₂OCH₃, SO₂—CH₂CH₂CF₂, SO₂—CH₂CH₂Cl, SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂CH₃,C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₃,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   α, β, ε, and ϕ are present;    -   χ and δ are absent;    -   Z₁ is N;    -   Z₂ is N; and    -   X is N.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein each        R₈ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl,        O(C₁-C₄ alkyl), CN, CF₃, C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂,        C(O)—NHCH₃, or NHC(O)—N(CH₃)₂

In some embodiments, the compound wherein IS has the structure:

In some embodiments, the compound wherein

-   -   each R₈ is independently H, Cl, Br, F, OCH₃, OCH₂CH₃, CF₃, CN,        CH₃, CH₃CH₃, C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,        NHC(O)—NHCH₃, NHC(O)—N(CH₃)₂, SO₂—NHCH₃ or SO₂—N(CH₃)₂.

In some embodiments, the compound wherein

-   -   α, χ, ε, and ϕ are present;    -   β and δ are absent;    -   Z₁ is O or S;    -   Z₂ is N; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein each        R₈ is independently H, halogen, O—(C₁-C₄ alkyl), CN, or CF₃.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

wherein

α, β, χ, and δ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₃ is CH, S, O, N or NRd,

-   -   wherein R₁₁ is H or C₁-C₁₀ alkyl;

Z₄ is CH, S, O, N or NR₁₂,

-   -   wherein R₁₂ is H or C₁-C₁₀ alkyl;

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

In some embodiments of the above compound, the compound wherein when αis present, then Z₃ are N, Z₄ is CH, X is N, β and δ are absent, and χis present;

when α is absent, then Z₃ is CH or N, Z₄ is NR₇, S, or O, X is C, β andδ are present, and χ is absent.

In some embodiments, the compound wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₃ is CH, S, O, N or NR₁₁,

-   -   wherein R₁₁ is H or C₁-C₁₀ alkyl;

Z₄ is CH, S, O, N or NR₁₂,

-   -   wherein R₁₂ is H or C₁-C₁₀ alkyl;

Y₁, Y₂, Y₃, and each occurrence of Y₄ are each independently CR₁₃,C(R₁₄)₂, N—R₁₅, O, N, SO₂, or C═O,

-   -   wherein    -   R₁₃ is H, halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀        alkyl), C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄        alkyl), C(O)—NH(C₁-C₄ alkyl)₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH(C₁-C₁₀ alkyl), SO₂—N(C₁-C₁₀        alkyl)₂, CN, CF₃, imidazole, morpholino, or pyrrolidine    -   R₁₄ is H or C₁-C₁₀ alkyl;    -   R₁₅ is H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃,        (C₁-C₁₀ alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl),        SO₂—(C₁-C₁₀ alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀        alkyl)-halogen, C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₁₀ alkyl)-CF₃,        C(O)—(C₁-C₁₀ alkyl)-OCH₃, C(O)—(C₁-C₁₀ alkyl)-halogen,        C(O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₁₀        alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments of the above compound, the compound wherein when αis present, then Z₃ are N, Z₄ is CH, X is N, β and δ are absent, and χis present;

when α is absent, then Z₃ is CH or N, Z₂ is NR₁₂, S, or O, X is C, β andδ are present, and χ is absent;

-   -   when ε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃,        and Y₄ are independently C—R₁₃ or N;

when ε and ϕ are each absent, then n=0, 1 or 2, each of Y₁, Y₂, Y₃, andeach occurrence of Y₄ are independently C(R₁₄)₂, N—R₁₅, O, or SO₂.

In some embodiments, the compound wherein

-   -   α, χ, ε, and ϕ are each present, β and δ are each absent, Z₃ is        CH, Z₄ is N; and X is N; or    -   χ, δ, ε, and ϕ are each present, α and β are each absent, Z₃ is        CH, Z₄ is N—R₁₂; and X is C; or    -   χ, δ, ε, and ϕ are each present, α and β are each absent, Z₃ is        N, Z₄ is N—R₁₂, S or O: and X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1; and    -   Y₁, Y₂, Y₁, and Y₄ are each C—R₁₃ or N,        -   wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH), C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃; or    -   Y₁ is N, and Y₂, Y₁, and Y₄ are each C—R₁₃.

In some embodiments, the compound wherein B has the structure:

-   -   wherein is R₁₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl,        O—(C₁-C₄ alkyl), C₁-C₄ cycloalkyl, C(O)OH, C(O)—NH₂,        C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, CF₃, imidazole,        morpholino, or pyrrolidine.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₁₂ is H or C₁-C₄ alkyl;    -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃ or N.        -   wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₃ is H, CH₃, CF₃, OCH₃, F,Cl,

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1; and    -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃ or N,        -   wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃, or one of Y₁, Y₂, Y₃, or Y₄        is N and the other three of Y₁, Y₂, Y₃, or Y₄ are each C—R₁₃,        -   wherein each R₁₃ is H.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₁₆, R₁₇, and R₁₈ are each H, halogen, C₁-C₄ alkyl or        C₁-C₄ cycloalkyl.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B is a substituted orunsubstituted monocycle or heteromonocycle.

In some embodiments, the compound wherein B is a substituted orunsubstituted imidazole, pyridazine, pyrazole, pyrazine, thiadiazole, ortriazole.

In some embodiments, the compound wherein wherein B has the structure:

-   -   wherein R₁₉ is H, halogen CN, CF₃, OH, NH₂, C₁-C₄ alkyl, C₃-C₆        cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂, C(O)NH(C₁-C₄ alkyl),        C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄ alkyl), C(O) (C₁-C₄        alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆        cycloalkyl), C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₄        alkyl), NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₄ alkyl) or tetrazole.

In some embodiments, the compound wherein R₁₉ is H, Cl, Br, F, OCH₃,OCH₂CH₃, CF₃, CN, CH₃, CH₃CH₃, COOH, or COOCH₃.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   R₂₀ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₄        alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,        NHC(O)—N(CH₃)₂, CN or CF₃.

In some embodiments, the compound wherein

-   -   R₂₀ is H, CH₃, or CH₂CH₃; and    -   R₂₁ is H, Cl, Br, F, OCH₃, OCH₂CH₃, CF₃, CN, CH₃, or CH₃CH₃.

In some embodiments, the compound wherein B is a substituted orunsubstituted phenyl, pyridine, pyrimidine, benzyl, pyrrolidine,sulfolane, oxetane, CO₂H or (C₁-C₄ alkyl)-CO₂H,

or

B is

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, CF₃, OH, NH₃, C₁-C₁₀ alkyl, C₃-C₄ cycloalkyl,        O(C₁-C₄ alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C10 alkyl), C(O)(C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl) or tetrazole.

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁, R₂₂, and R₂₃ are each independently H, halogen, OH,        CF₃, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl),        C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH,        C(O)O(C₁-C₄ alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄        alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, and R₂₃ are eachindependently F, Cl, CH₃, CF₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein a has the structure:

wherein R₂₂, R₂₃, R₂₄ and R₂₅ are each independently H, halogen, OH,CF₃, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄ alkyl),C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆cycloalkyl), C(O)NH(SO₂)-(aryl), or O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₂, R₂₃, R₂₄ and R₂₅ are eachindependently H, F, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH), C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein R₂₂, R₂₄, R₂₅ are each H andR₂₃ is F, Cl, CH₃, CF₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, CF₃, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl,        O(C₁-C₁₀ alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)(C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₁₀ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl).

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁ and R₂₅ are each independently H, halogen, OH, NH₂,        C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁ and R₂₅ are eachindependently P, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen, OH, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl),        C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH,        C(O)O(C₁-C₄ alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄        alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₃, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, R₂₃, R₂₄ and R₂₅ areeach independently H, P, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂,C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein R₂₂, R₂₄, R₂₅ are each H andR₂₃ is F, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, CF₃, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl,        O(C₁-C₁₀ alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)(C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₁₀ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl).

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₂₁, R₂₂, R₂₄ and R₂₅ are each independently H, halogen,        OH, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H, F, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein B has the structure

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, R₄, and R₅ are each H, t-Bu, Cl, F, or CF₃.

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, and R₄ are each H; and    -   R₅ is CF₃.

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, and R₄ are each H; and    -   R₅ is t-Bu.

In some embodiments, the compound having the structure:

The present invention provides a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptablecarrier.

The present invention provides a method for treating a diseasecharacterized by excessive lipofuscin accumulation in the retina in amammal afflicted therewith comprising administering to the mammal aneffective amount of a compound of the present invention or a compositionof the present invention.

In some embodiments of the method, wherein the disease is furthercharacterized by bisretinoid-mediated macular degeneration.

In some embodiments of the method, wherein the amount of the compound iseffective to lower the serum concentration of RBP4 in the mammal.

In some embodiments of the method, wherein the amount of the compound iseffective to lower the retinal concentration of a bisretinoid inlipofuscin in the mammal.

In some embodiments of the method, wherein the bisretinoid is A2E.

In some embodiments of the method, wherein the bisretinoid is isoA2E. Insome embodiments of the method, wherein the bisretinoid is A2-DHP-PE. Insome embodiments of the method, wherein the bisretinoid is atRAL di-PE.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Age-Related MacularDegeneration.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is dry (atrophic)Age-Related Macular Degeneration.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Stargardt Disease.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Best disease.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is adult vitelliformmaculopathy.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Stargardt-likemacular dystrophy.

In some embodiments, B has the structure:

In some embodiments, bisretinoid-mediated macular degeneration isAge-Related Macular Degeneration or Stargardt Disease.

In some embodiments, the bisretinoid-mediated macular degeneration isAge-Related Macular Degeneration.

In some embodiments, the bisretinoid-mediated macular degeneration isdry (atrophic) Age-Related Macular Degeneration.

In some embodiments, the bisretinoid-mediated macular degeneration isStargardt Disease.

In some embodiments, the bisretinoid-mediated macular degeneration isBest disease.

In some embodiments, the bisretinoid-mediated macular degeneration isadult vitelliform maculopathy.

In some embodiments, the bisretinoid-mediated macular degeneration isStargardt-like macular dystrophy.

The bisretinoid-mediated macular degeneration may comprise theaccumulation of lipofuscin deposits in the retinal pigment epithelium.

As used herein, “bisretinoid lipofuscin” is lipofuscin containing acytotoxic bisretinoid. Cytotoxic bisretinoids include but are notnecessarily limited to A2E, isoA2E, atRAL di-PE, and A2-DHP-PE (FIGS. 1,2, and 3).

Except where otherwise specified, when the structure of a compound ofthis invention includes an asymmetric carbon atom, it is understood thatthe compound occurs as a racemate, racemic mixture, and isolated singleenantiomer. All such isomeric forms of these compounds are expresslyincluded in this invention. Except where otherwise specified, eachstereogenic carbon may be of the R or S configuration. It is to beunderstood accordingly that the isomers arising from such asymmetry(e.g., all enantiomers and diastereomers) are included within the scopeof this invention, unless indicated otherwise. Such isomers can beobtained in substantially pure form by classical separation techniquesand by stereochemically controlled synthesis, such as those described in“Enantiomers, Racemates and Resolutions” by J. Jacques, A. Collet and S.Wilen, Pub. John Wiley & Sons, N Y, 1981. For example, the resolutionmay be carried out by preparative chromatography on a chiral column.

The subject invention is also intended to include all isotopes of atomsoccurring on the compounds disclosed herein. Isotopes include thoseatoms having the same atomic number but different mass numbers. By wayof general example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

It will be noted that any notation of a carbon in structures throughoutthis application, when used without further notation, are intended torepresent all isotopes of carbon, such as ¹²C, ¹³C, or ¹⁴C. Furthermore,any compounds containing ¹³C or ¹⁴C may specifically have the structureof any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structuresthroughout this application, when used without further notation, areintended to represent all isotopes of hydrogen, such as ¹H, ²H, or ³H.Furthermore, any compounds containing ²H or ³H may specifically have thestructure of any of the compounds disclosed herein.

Isotopically-labeled compounds can generally be prepared by conventionaltechniques known to those skilled in the art using appropriateisotopically-labeled reagents in place of the non-labeled reagentsemployed.

The term “substitution”, “substituted”, and “substituent” refers to afunctional group as described above in which one or more bonds to ahydrogen atom contained therein are replaced by a bond to non-hydrogenor non-carbon atoms, provided that normal valencies are maintained andthat the substitution results in a stable compound. Substituted groupsalso include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom are replaced by one or more bonds, including double ortriple bonds, to a heteroatom. Examples of substituent groups includethe functional groups described above, and halogens (i.e., F, Cl, Br,and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl,n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, suchas methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such asphenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) andp-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy);heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl,methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto;sulfanyl groups, such as methylsulfanyl, ethylsulfanyl andpropylsulfanyl; cyano; amino groups, such as amino, methylamino,dimethylamino, ethylamino, and diethylamino; and carboxyl. Wheremultiple substituent moieties are disclosed or claimed, the substitutedcompound can be independently substituted by one or more of thedisclosed or claimed substituent moieties, singly or plurally. Byindependently substituted, it is meant that the (two or more)substituents can be the same or different.

In the compounds used in the method of the present invention, thesubstituents may be substituted or unsubstituted, unless specificallydefined otherwise.

In the compounds used in the method of the present invention, alkyl,heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groupscan be further substituted by replacing one or more hydrogen atoms withalternative non-hydrogen groups. These include, but are not limited to,halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

It is understood that substituents and substitution patterns on thecompounds used in the method of the present invention can be selected byone of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art from readily available starting materials. If asubstituent is itself substituted with more than one group, it isunderstood that these multiple groups may be on the same carbon or ondifferent carbons, so long as a stable structure results.

In choosing the compounds used in the method of the present invention,one of ordinary skill in the art will recognize that the varioussubstituents, i.e. R₁, R₂, etc. are to be chosen in conformity withwell-known principles of chemical structure connectivity.

As used herein, “alkyl” includes both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms and may be unsubstituted or substituted. Thus, C₁-C_(n) asin “C₁-C_(n) alkyl” is defined to include groups having 1, 2 . . . , n−1or n carbons in a linear or branched arrangement. For example, C₁-C₆, asin “C₁-C₆ alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6carbons in a linear or branched arrangement, and specifically includesmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, and hexyl.Unless otherwise specified contains one to ten carbons. Alkyl groups canbe unsubstituted or substituted with one or more substituents, includingbut not limited to halogen, alkoxy, alkylthio, trifluoromethyl,difluoromethyl, methoxy, and hydroxyl.

As used herein, “C₁-C₄ alkyl” includes both branched and straight-chainC₁-C₄ alkyl.

As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical,straight or branched, containing at least 1 carbon to carbon doublebond, and up to the maximum possible number of non-aromaticcarbon-carbon double bonds may be present, and may be unsubstituted orsubstituted. For example, “C₂-C₆ alkenyl” means an alkenyl radicalhaving 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5carbon-carbon double bonds respectively. Alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl.

As used herein, “heteroalkyl” includes both branched and straight-chainsaturated aliphatic hydrocarbon groups having at least 1 heteroatomwithin the chain or branch.

As used herein, “cycloalkyl” includes cyclic rings of alkanes of threeto eight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

As used herein, “heterocycloalkyl” is intended to mean a 5- to10-membered nonaromatic ring containing from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S, and includes bicyclic groups.“Heterocyclyl” therefore includes, but is not limited to the following:imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl,tetrahydrothiophenyl and the like. If the heterocycle contains nitrogen,it is understood that the corresponding N-oxides thereof are alsoencompassed by this definition.

As used herein, “aryl” is intended to mean any stable monocyclic,bicyclic or polycyclic carbon ring of up to 10 atoms in each ring,wherein at least one ring is aromatic, and may be unsubstituted orsubstituted. Examples of such aryl elements include but are not limitedto: phenyl, p-toluenyl(4-methylphenyl), naphthyl, tetrahydro-naphthyl,indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the arylsubstituent is bicyclic and one ring is non-aromatic, it is understoodthat attachment is via the aromatic ring.

The term “alkylaryl” refers to alkyl groups as described above whereinone or more bonds to hydrogen contained therein are replaced by a bondto an aryl group as described above. It is understood that an“alkylaryl” group is connected to a core molecule through a bond fromthe alkyl group and that the aryl group acts as a substituent on thealkyl group. Examples of arylalkyl moieties include, but are not limitedto, benzyl (phenylmethyl),p-trifluoromethylbenzyl(4-trifluoromethylphenylmethyl), 1-phenylethyl,2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.

The term “heteroaryl” as used herein, represents a stable monocyclic,bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein atleast one ring is aromatic and contains from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S. Bicyclic aromatic heteroarylgroups include but are not limited to phenyl, pyridine, pyrimidine orpyridizine rings that are (a) fused to a 6-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a5- or 6-membered aromatic (unsaturated) heterocyclic ring having twonitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated)heterocyclic ring having one nitrogen atom together with either oneoxygen or one sulfur atom; or (d) fused to a 5-membered aromatic(unsaturated) heterocyclic ring having one heteroatom selected from O, Nor S. Heteroaryl groups within the scope of this definition include butare not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl,indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl,oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl,1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl,furanyl, thienyl, benzothienyl, benzofuranyl quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where theheteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Ifthe heteroaryl contains nitrogen atoms, it is understood that thecorresponding N-oxides thereof are also encompassed by this definition.

As used herein, “monocycle” includes any stable polycyclic carbon ringof up to 10 atoms and may be unsubstituted or substituted. Examples ofsuch non-aromatic monocycle elements include but are not limited to:cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of sucharomatic monocycle elements include but are not limited to: phenyl. Asused herein, “heteromonocycle” includes any monocycle containing atleast one heteroatom.

As used herein, “bicycle” includes any stable polycyclic carbon ring ofup to 10 atoms that is fused to a polycyclic carbon ring of up to 10atoms with each ring being independently unsubstituted or substituted.Examples of such non-aromatic bicycle elements include but are notlimited to: decahydronaphthalene. Examples of such aromatic bicycleelements include but are not limited to: naphthalene. As used herein,“heterobicycle” includes any bicycle containing at least one heteroatom.

The term “phenyl” is intended to mean an aromatic six membered ringcontaining six carbons, and any substituted derivative thereof.

The term “benzyl” is intended to mean a methylene attached directly to abenzene ring. A benzyl group is a methyl group wherein a hydrogen isreplaced with a phenyl group, and any substituted derivative thereof.

The term “pyridine” is intended to mean a heteroaryl having asix-membered ring containing 5 carbon atoms and 1 nitrogen atom, and anysubstituted derivative thereof.

The term “pyrimidine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are separated by one carbon atom, and anysubstituted derivative thereof.

The term “pyridazine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are adjacent to each other, and any substitutedderivative thereof.

The term “pyrazine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are separated by two carbon atoms, and anysubstituted derivative thereof.

The term “pyrrolidine” is intended to mean a non-aromatic five-memberedring containing four carbon atoms and one nitrogen atom, and anysubstituted derivative thereof.

The term “triazole” is intended to mean a heteroaryl having afive-membered ring containing two carbon atoms and three nitrogen atoms,and any substituted derivative thereof.

The term “imidazole” is intended to mean a heteroaryl having afive-membered ring containing three carbon atoms and two nitrogen atoms,and any substituted derivative thereof.

The term “thiadiazole” is intended to mean a heteroaryl having afive-membered ring containing two carbon atoms, two nitrogen atoms, andone sulfur atom and any substituted derivative thereof.

The term “pyrazole” is intended to mean a heteroaryl having afive-membered ring containing three carbon atoms and two nitrogen atomswherein the nitrogen atoms are adjacent to each other, and anysubstituted derivative thereof.

The term “triazine” is intended to mean a heteroaryl having asix-membered ring containing 3 carbon atoms and 3 nitrogen atoms, andany substituted derivative thereof.

The term “indole” is intended to mean a heteroaryl having afive-membered ring fused to a phenyl ring with the five-membered ringcontaining 1 nitrogen atom directly attached to the phenyl ring.

The term “benzimidazole” is intended to mean a heteroaryl having afive-membered ring fused to a phenyl ring with the five-membered ringcontaining 2 nitrogen atoms directly attached to the phenyl ring.

The term “oxatane” is intended to mean a non-aromatic four-membered ringcontaining three carbon atoms and one oxygen atom, and any substitutedderivative thereof.

The term “sulfolane” is intended to mean a non-aromatic five-memberedring containing four carbon atoms and one sulfur atom wherein the sulfuratom is doubly bonded to two oxygen atoms and any substituted derivativethereof.

The compounds used in the method of the present invention may beprepared by techniques well know in organic synthesis and familiar to apractitioner ordinarily skilled in the art. However, these may not bethe only means by which to synthesize or obtain the desired compounds.

The compounds of present invention may be prepared by techniquesdescribed in Vogel's Textbook of Practical Organic Chemistry, A. I.Vogel, A. R. Tatchell, B. S. Furnis, A. J. Hannaford, P. W. G. Smith,(Prentice Hall) 5^(th) Edition (1996), March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, JerryMarch, (Wiley-Interscience) 5^(th) Edition (2007), and referencestherein, which are incorporated by reference herein. However, these maynot be the only means by which to synthesize or obtain the desiredcompounds.

The compounds of present invention may be prepared by techniquesdescribed herein. The synthetic methods used to prepare Examples 51-52may be used to prepare additional octahydropyrrolopyrroles compoundswhich described herein.

The various R groups attached to the aromatic rings of the compoundsdisclosed herein may be added to the rings by standard procedures, forexample those set forth in Advanced Organic Chemistry: Part B: Reactionand Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed.Edition. (2007), the content of which is hereby incorporated byreference.

Another aspect of the invention comprises a compound of the presentinvention as a pharmaceutical composition.

As used herein, the term “pharmaceutically active agent” means anysubstance or compound suitable for administration to a subject andfurnishes biological activity or other direct effect in the treatment,cure, mitigation, diagnosis, or prevention of disease, or affects thestructure or any function of the subject. Pharmaceutically active agentsinclude, but are not limited to, substances and compounds described inthe Physicians' Desk Reference (PDR Network, LLC; 64th edition; Nov. 15,2009) and “Approved Drug Products with Therapeutic EquivalenceEvaluations” (U.S. Department Of Health And Human Services, 30^(th)edition. 2010), which are hereby incorporated by reference.Pharmaceutically active agents which have pendant carboxylic acid groupsmay be modified in accordance with the present invention using standardesterification reactions and methods readily available and known tothose having ordinary skill in the art of chemical synthesis. Where apharmaceutically active agent does not possess a carboxylic acid group,the ordinarily skilled artisan will be able to design and incorporate acarboxylic acid group into the pharmaceutically active agent whereesterification may subsequently be carried out so long as themodification does not interfere with the pharmaceutically active agent'sbiological activity or effect.

The compounds of the present invention may be in a salt form. As usedherein, a “salt” is a salt of the instant compounds which has beenmodified by making acid or base salts of the compounds. In the case ofcompounds used to treat a disease, the salt is pharmaceuticallyacceptable. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines; alkali or organic salts of acidic residues such as phenols.The salts can be made using an organic or inorganic acid. Such acidsalts are chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, and the like. Phenolate salts are the alkalineearth metal salts, sodium, potassium or lithium. The term“pharmaceutically acceptable salt” in this respect, refers to therelatively non-toxic, inorganic and organic acid or base addition saltsof compounds of the present invention. These salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound of theinvention in its free base or free acid form with a suitable organic orinorganic acid or base, and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

As salt or pharmaceutically acceptable salt is contemplated for allcompounds disclosed herein.

As used herein, “treating” means preventing, slowing, halting, orreversing the progression of a disease or infection. Treating may alsomean improving one or more symptoms of a disease or infection.

The compounds of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compoundmay be a component of a combination therapy or an adjunct therapy, i.e.the subject or patient in need of the drug is treated or given anotherdrug for the disease in conjunction with one or more of the instantcompounds. This combination therapy can be sequential therapy where thepatient is treated first with one drug and then the other or the twodrugs are given simultaneously. These can be administered independentlyby the same route or by two or more different routes of administrationdepending on the dosage forms employed.

As used herein, a “pharmaceutically acceptable carrier” is apharmaceutically acceptable solvent, suspending agent or vehicle, fordelivering the instant compounds to the animal or human. The carrier maybe liquid or solid and is selected with the planned manner ofadministration in mind. Liposomes are also a pharmaceutically acceptablecarrier.

The dosage of the compounds administered in treatment will varydepending upon factors such as the pharmacodynamic characteristics of aspecific chemotherapeutic agent and its mode and route ofadministration; the age, sex, metabolic rate, absorptive efficiency,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment being administered; thefrequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds used in the method of the presentinvention may comprise a single compound or mixtures thereof withadditional agents. The compounds can be administered in oral dosageforms as tablets, capsules, pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. The compounds may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, or introduced directly, e.g. byinjection, topical application, or other methods, into or onto a site ofinfection, all using dosage forms well known to those of ordinary skillin the pharmaceutical arts.

The compounds used in the method of the present invention can beadministered in admixture with suitable pharmaceutical diluents,extenders, excipients, or carriers (collectively referred to herein as apharmaceutically acceptable carrier) suitably selected with respect tothe intended form of administration and as consistent with conventionalpharmaceutical practices. The unit will be in a form suitable for oral,rectal, topical, intravenous or direct injection or parenteraladministration. The compounds can be administered alone or mixed with apharmaceutically acceptable carrier. This carrier can be a solid orliquid, and the type of carrier is generally chosen based on the type ofadministration being used. The active agent can be co-administered inthe form of a tablet or capsule, liposome, as an agglomerated powder orin a liquid form. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Capsule or tablets can be easily formulatedand can be made easy to swallow or chew; other solid forms includegranules, and bulk powders. Tablets may contain suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Examples of suitableliquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents. Oral dosage formsoptionally contain flavorants and coloring agents. Parenteral andintravenous forms may also include minerals and other materials to makethem compatible with the type of injection or delivery system chosen.

Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa. 1985); Advances in Pharmaceutical Sciences (David Ganderton,Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7.(David Ganderton, Trevor Jones, James McGinity, Eds., 1995); AqueousPolymeric Coatings for Pharmaceutical Dosage Forms (Drugs and thePharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds used in the method of the present invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamallar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines. The compounds maybe administered as components of tissue-targeted emulsions.

The compounds used in the method of the present invention may also becoupled to soluble polymers as targetable drug carriers or as a prodrug.Such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and crosslinked or amphipathicblock copolymers of hydrogels.

Gelatin capsules may contain the active ingredient compounds andpowdered carriers, such as lactose, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as immediate release products or as sustained releaseproducts to provide for continuous release of medication over a periodof hours. Compressed tablets can be sugar coated or film coated to maskany unpleasant taste and protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract.

For oral administration in liquid dosage form, the oral drug componentsare combined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Examples ofsuitable liquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The compounds used in the method of the present invention may also beadministered in intranasal form via use of suitable intranasal vehicles,or via transdermal routes, using those forms of transdermal skin patcheswell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill generally be continuous rather than intermittent throughout thedosage regimen.

Parenteral and intravenous forms may also include minerals and othermaterials to make them compatible with the type of injection or deliverysystem chosen.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS

Materials and Methods

TR-FRET Assay for Retinol-induced RBP4-TTR Interaction

Binding of a desired RBP4 antagonist displaces retinol and induceshindrance for RBP4-TTR interaction resulting in the decreased FRETsignal (FIG. 7). Bacterially expressed MBP-RBP4 and untagged TTR wereused in this assay. For the use in the TR-FRET assay the maltose bindingprotein (MBP)-tagged human RBP4 fragment (amino acids 19-201) wasexpressed in the Gold(DE3)pLysS E. coli strain (Stratagene) using thepMAL-c4x vector. Following cell lysis, recombinant RBP4 was purifiedfrom the soluble fraction using the ACTA FPLC system (GE Healthcare)equipped with the 5-ml the MBP Trap HP column. Human untagged TTR waspurchased from Calbiochem. Untagged TTR was labeled directly with Eu³⁺Cryptate-NHS using the HTRF Cryptate Labeling kit from CisBio followingthe manufacturer's recommendations. HTRF assay was performed in whitelow volume 384 well plates (Greiner-Bio) in a final assay volume of 16μl per well. The reaction buffer contained 10 mM Tris-HCl pH 7.5, 1 mMUDT, 0.05% NP-40. 0.05% Prionex, 6% glycerol, and 400 mM KF. Eachreaction contained 60 nM MBP-RBP4 and 2 nM TTR-Eu along with 26.7 nM ofanti-MBP antibody conjugated with d2 (Cisbio). Titration of testcompounds in this assay was conducted in the presence of 1 μM retinol.All reactions were assembled in the dark under dim red light andincubated overnight at +4° C. wrapped in aluminum foil. TR-FRET signalwas measured in the SpectraMax M5e Multimode Plate Reader (MolecularDevice). Fluorescence was excited at 337 nm and two readings per wellwere taken: Reading 1 for time-gated energy transfer from Eu(K) to d2(337 nm excitation, 668 nm emission, counting delay 75 microseconds,counting window 100 microseconds) and Reading 2 for Eu(K) time-gatedfluorescence (337 nm excitation, 620 nm emission, counting delay 400microseconds, counting window 400 microseconds). The TR-FRET signal wasexpressed as the ratio of fluorescence intensity: Flu₆₆₅/Flu₆₂₀×10,000.

Scintillation Proximity RBP4 Binding Assay

Untagged human RBP4 purified from urine of tubular proteinuria patientswas purchased from Fitzgerald Industries International. It wasbiotinylated using the EZ-Link Sulfo-NHS-LC-Biotinylation kit fromPierce following the manufacturer's recommendations. Binding experimentswere performed in 96-well plates (OptiPlate, PerkinElmer) in a finalassay volume of 100 μl per well in SPA buffer (1×PBS, pH 7.4, 1 mM EDTA,0.1% BSA, 0.5% CHAPS). The reaction mix contained 10 nM ³H-Retinol (48.7Ci/mmol; PerkinElmer), 0.3 mg/well Streptavidin-PVT beads, 50 nMbiotinylated RBP4 and a test compound. Nonspecific binding wasdetermined in the presence of 20 μM of unlabeled retinol. The reactionmix was assembled in the dark under dim red light. The plates weresealed with clear tape (TopSeal-A: 96-well microplate, PerkinElmer),wrapped in the aluminum foil, and allowed to equilibrate 6 hours at roomtemperature followed by overnight incubation at +4° C. Radiocounts weremeasured using a TopCount NXT counter (Packard Instrument Company).

General Procedures for Preparing 3.3.0 Octahydrocylopena[c]pyrrole AmideII

Conditions: A1) carboxylic acid, HBTU, Et₃N, DMF; A2) carboxylic acid,EDCI, HOBt, I-Pr₂NEt, DMF; A3) acid chloride, Et₃N, CH₂Cl².

General Procedure (GP-A1) for Carboxamide Formation: A mixture of amineI (1 equiv), desired carboxylic acid (1 equiv), triethylamine (Et₃N) (3equiv), and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphate (HBTU) (1.5 equiv) in DMF (0.25 M) was stirred atroom temperature until the reaction was complete by TLC or LC-MS. Themixture was diluted with H₂O and extracted with EtOAc. The combinedorganic extracts were washed with H₂O, brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by either normal phase silica gel column chromatography(typical eluents included either a mixture of or hexanes and EtOAc or amixture of CH₂Cl₂ and a 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentratedNH₄OH) or C-18 reversed phase column chromatography (typical eluentsincluded CH₃CN and H₂O) to afford the desired carboxamide II. Theproduct structure was verified by ¹H NMR and by mass analysis.

General Procedure (CP-A2) for carboxamide formation: A mixture of amineI (1 equiv), desired carboxylic acid (1 equiv), N,N-diisopropylethylamine (i-PraNEt) (3 equiv),1-ethyl-3-(3-dimethylaminutesopropyl)carbodiimide (EDCI) (1.5 equiv) andhydroxybenzotriazole (HOBt) (1.5 equiv) in EMF (0.25 M) was stirred atroom temperature until the reaction was complete by TLC or LC-MS. Themixture was diluted with H₂O and extracted with EtOAc. The combinedorganic extracts were washed with H₂O, brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by either normal phase silica gel column chromatography(typical eluents included either a mixture of or hexanes and EtOAc or amixture of CH₂Cl₂ and a 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentratedNH₄OH) or C-18 reversed phase column chromatography (typical eluentsincluded CH₃CN and H₂O) to afford the desired carboxamide II. Theproduct structure was verified by ¹H NMR and by mass analysis.

General Procedure (GP-A3) for Carboxamide Formation: A mixture of amineI (1 equiv), Et₃N (3 equiv), and acid chloride (1 equiv) in CH₂Cl₂ (0.25M) was stirred at room temperature until the reaction was complete byTLC or LC-MS. The mixture was washed with H₂O, brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by either normal phase silica gel column chromatography(typical eluents included either a mixture of or hexanes and EtOAc or amixture of CH₂Cl₂ and a 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentratedNH₄OH) or C-18 reversed phase column chromatography (typical eluentsincluded CH₃CN and H₂O) to afford the desired carboxamides II. Theproduct structure was verified by ¹H NMR and by mass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanoneCarboxamides IV

Conditions: B) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-B) for carboxamide formation: A mixture of amineIII (1 equiv), desired acid chloride (1 equiv) and Et₃N (3 equiv) inCH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperature until thereaction was complete by TLC or LC-MS. The mixture was diluted with H₂Oand extracted with CH₂Cl₂. The combined organic extracts were washedwith H₂O brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by either normalphase silica gel column chromatography (typical eluents included eithera mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phasecolumn chromatography (typical eluents included CH₃CN and H₂O) to affordthe desired carboxamides IV. The product structure was verified by ¹HNMR and by mass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanoneSulfonamides V

Conditions: C) sulfonyl chloride, i-Pr₂NEt, CH₂Cl₂.

General Procedure (GP-C) for sulfonamide formation: A mixture of amineIII (1 equiv), desired sulfonyl chloride (1 equiv) and i-Pr₂NEt (3equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperatureuntil the reaction was complete by TLC or LC-MS. The mixture was dilutedwith H₂O and extracted with CH₂Cl₂. The combined organic extracts werewashed with H₂O, brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resulting residue was purified by eithernormal phase silica gel column chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversedphase column chromatography (typical eluents included CH₃CN and H₂O) toafford the desired sulfonamides V. The product structure was verified by¹H NMR and by mass analysis.

General Procedures for Preparing Alkylated(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanoneVI

Conditions: D) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-D) for sulfonamide formation: A mixture of amineIII (1 equiv), desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv)in CH₂Cl₂ (0.25 M) was stirred for 16 hours at room temperature. To thiswas added sodium triacetoxyborohydride (NaBH(OAc)₃) and the mixturestirred at room temperature until the reaction was complete by TLC orLC-MS. The mixture was diluted with aqueous, saturated NaHCO₃ solutionand extracted with CH₂Cl₂. The combined organic extracts were washedwith H₂O, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by either normalphase silica gel column chromatography (typical eluents included eithera mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phasecolumn chromatography (typical eluents included CH₃CN and H₂O) to affordthe desired amines VI. The product structure was verified by ¹H NMR andby mass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanoneCarboxamides VIII

Conditions: E) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-E) for carboxamide formation: A mixture of amineVII (1 equiv), desired acid chloride (1 equiv) and Et₃N (3 equiv) inCH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperature until thereaction was complete by TLC or LC-MS. The mixture was diluted with H₂Oand extracted with CH₂Cl₂. The combined organic extracts were washedwith H₂O, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by either normalphase silica gel column chromatography (typical eluents included eithera mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phasecolumn chromatography (typical eluents included CH₃CN and H₂O) to affordthe desired carboxamides VIII. The product structure was verified by ¹HNR and by mass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanoneSulfonamides IX

Conditions: F) sulfonyl chloride, i-Pr₂NEt, CH₃Cl₂.

General Procedure (GP-F) for sulfonamide formation: A mixture of amineVII (1 equiv), desired sulfonyl chloride (1 equiv) and i-Pr₂NEt (3equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperatureuntil the reaction was complete by TLC or LC-MS. The mixture was dilutedwith H₂O and extracted with CH₂Cl₂. The combined organic extracts werewashed with H₂O, brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resulting residue was purified by eithernormal phase silica gel column chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversedphase column chromatography (typical eluents included CH₃CN and H₂O) toafford the desired sulfonamides tt. The product structure was verifiedby ¹H NMR and by mass analysis.

General Procedures for Preparing Alkylated(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanonesX

Conditions: G) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-G) for Sulfonamide Formation: A mixture of amineVII (1 equiv), desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv)in CH₂Cl₂ (0.25 M) was stirred for 16 hours at room temperature. To thiswas added NaBH(OAc)₃ and the mixture stirred at room temperature untilthe reaction was complete by TLC or LC-NS. The mixture was diluted withaqueous, saturated NaHCO₃ solution and extracted with CH₂Cl₂. Thecombined organic extracts were washed with H₂O, brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was purified by either normal phase silica gel columnchromatography (typical eluents included either a mixture of or hexanesand EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phase columnchromatography (typical eluents included CH₃CN and H₂O) to afford thedesired amine X. The product structure was verified by ¹H NMR and bymass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanoneCarboxamides XII

Conditions: H) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-H) for carboxamide formation: A mixture of amineXI (1 equiv), desired acid chloride (1 equiv) and Et₃N (3 equiv) inCH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperature until thereaction was complete by TLC or LC-MS. The mixture was diluted with H₂Oand extracted with CH₂Cl₂. The combined organic extracts were washedwith H₂O, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by either normalphase silica gel column chromatography (typical eluents included eithera mixture of or hexanes and EtOAc or a mixture of CH₃Cl₂ and a 90:9:1mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phasecolumn chromatography (typical eluents included CH₃CN and H₂O) to affordthe desired carboxamides XII. The product structure was verified by ¹HNMR and by mass analysis.

General Procedures for Preparing(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrzzol-3-yl)methanoneSulfonamides XIII

Conditions: I) sulfonyl chloride, i-Pr₂NEt, CH₂Cl₂.

General Procedure (GP-I) for Sulfonamide Formation: A mixture of amineXI (1 equiv), desired sulfonyl chloride (1 equiv) and i-Pr₂NEt (3 equiv)in CH₂Cl₂ (0.25 M) was stirred from 0° C. to room temperature until thereaction was complete by TLC or LC-MS. The mixture was diluted with H₂Oand extracted with CH₂Cl₂. The combined organic extracts were washedwith H₂O, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by either normalphase silica gel column chromatography (typical eluents included eithera mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phasecolumn chromatography (typical eluents included CH₃CN and H₂O) to affordthe desired sulfonamides XIII. The product structure was verified by ¹HNMR and by mass analysis.

General Procedures for Preparing Alkylated(5-Phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyridin-3-yl)methanoneXIV

Conditions: J) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-J) for sulfonamide formation: A mixture of amineXI (1 equiv), desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv)in CH₂Cl₂ (0.25 M) was stirred for 16 hours at room temperature. To thiswas added NaBH(OAc)₃ and the mixture stirred at room temperature untilthe reaction was complete by TLC or LC-MS. The mixture was diluted withaqueous, saturated NaHCO₃ solution and extracted with CH₂Cl₂. Thecombined organic extracts were washed with H₂O, brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was purified by either normal phase silica gel columnchromatography (typical eluents included either a mixture of or hexanesand EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversed phase columnchromatography (typical eluents included CH₃CN and H₂O) to afford thedesired amine XIV. The product structure was verified by ¹H NMR and bymass analysis.

General Procedures for Preparing 3.3.0 Methyl2-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate XV

Conditions: K1) Et₃N, DMF

General Procedure (GP-K1) for 2-aminopyrimidine Formation: A mixture ofamine I (1 equiv), desired methyl 2-chloropyrimidine-4-carboxylate (1equiv), and triethylamine (Et₃N) (3 equiv) in DMF (0.25 M) was stirredat 60° C. until the reaction was complete by TLC or LC-MS. The mixturewas diluted with H₂O and extracted with EtOAc. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby either normal phase silica gel column chromatography (typical eluentsincluded either a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂and a 90:9:1 mixture of CH₃Cl₃/CH₃OH/concentrated NH₄OH) or C-18reversed phase column chromatography (typical eluents included CH₃CN andH₂O) to afford the desired carboxamide XV. The product structure wasverified by ¹H NMR and by mass analysis.

General Procedures for Preparing 3.3.02-(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylic Acid

Conditions: L1) 2N NaOH, CH₃OH, THF

General Procedure (GP-L1) for Carboxylic Acid Formation: A mixture ofester XV (1 equiv) and aqueous 2 N NaOH (3 equiv) in a 1:1 mixture ofTHF and CH₃OH (0.25 M) was stirred at room temperature until thereaction was complete by TLC or LC-MS. The mixture was neutralized with2 N HCl and extracted with CH₂Cl₂. The combined organic extracts werewashed with H₂O, brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resulting residue was purified by eithernormal phase silica gel column chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversedphase column chromatography (typical eluents included CH₃CN and H₂O) toafford the desired carboxamide XVI. The product structure was verifiedby ¹H NMR and by mass analysis.

Preparation of (3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole Hydrochloride (9)

Step A: To a 0° C. cooled solution of lithium aluminum hydride (LiAlH₄)in THF (1.0 M, 800 mL, 0.8 mol) in THF (800 mL) in a 3-L, three-necked,round-bottomed flask equipped with a thermometer was carefully added(3aR,7aS)-3,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (53.7 g, 0.35mol) portion-wise. An exotherm of −5° C. occurred upon each addition ofthe dione. Upon complete addition, the mixture was allowed to warm toroom temperature followed by heating at 70° C. for 16 hours. Thereaction was allowed to cool back to room temperature and then furthercooled to 0° C. The reaction was carefully quenched by slow addition ofH₂O (30 mL), 15% aqueous NaOH solution (30 mL), followed by anotherbolus of H₂O (90 mL). The rate of quenching was done carefully so as tomaintain an internal temperature below 25° C. The mixture stirred for 1hour and was filtered through Celite. The aqueous filtrate was extractedwith Et₂O (2×100 mL) and the organic extracts were combined andconcentrated under reduced pressure. The resulting residue was purifiedusing a Kugelrorh distillation apparatus to give(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-isoindole (2) as a clear, colorlessoil (19.45 g, 44%): ¹H NMR (500 MHz, CDCl₃) δ 5.29 (s, 2H), 3.88 (bs,1H), 3.26 (m, 2H), 2.82 (m, 2H), 2.41-2.19 (m, 4H), 1.96 (m, 2H).

Step B: To a 0° C. cooled solution of(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-isoindole (2, 11.5 g, 93.5 mmol) inCH₂Cl₂ (200 mL) was added di-tert-butyl dicarbonate (24.5 g, 112 mmol)and the mixture was allowed to stir at room temperature for 16 hours.The mixture was washed with H₂O (100 mL), brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography (Isco CombiFlash Rf unit,330 g Redisep column, 0% to 30% EtOAc in hexanes) to give(3aR,7aS)-tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (3) as a an oil (20.10g, 49%): ¹H NMR (500 MHz, CDCl₃) δ 5.64 (s, 2H), 3.39 (m, 2H), 3.20 (m,2H), 3.15 (m, 2H), 2.23-2.19 (m, 4H), 1.97 (m, 2H), 1.57 (s, 9H).

Step C: To a 0° C. cooled mixture of (3aR,7aS)-tert-butyl3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (3, 66.78 g, 0.224mol) in CH₃CN (600 mL), CCl₄ (400 ma), and H₂O (800 ma) was added NaIO₄(192.3 g, 0.899 mol) followed by RuO₂. H₂O (1.19 g, 8.94 mmol). Themixture was stirred at room temperature for 24 hours with mechanicalstirring and then filtered through Celite. The filter cake was washedwith 10% CH₃OH in CH₂Cl₂ (200 mL) and the biphasic mother liquor wasseparated. The aqueous phase was further extracted with CH₂Cl₂ (3×150mL) and the combined organic extracts were washed with H₂O (100 mL),brine (100 mL), dried over Na₃SO₄, filtered, and concentrated underreduced pressure. The residue was filtered through a plug of silica gelusing a CH₃OH/CH₂Cl₂ eluent system (2% to 10% CH₃OH in CH₂Cl₂). Thefiltrate was concentrated under reduced pressure to give2,2′-((3S,4R)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid(4) as a solid (46.75 g, 72%): ¹H NMR (500 MHz, DMSO-d₆) δ 12.2 (s, 2H),3.38 (m, 2H), 3.02 (m, 2H), 2.49 (m, 2H), 2.32 (m, 2H), 2.29 (m, 2H),1.42 (s, 9H).

Step D: To a suspension of 2,2′-((3S,4R)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (4, 6.97 g, 24.3 mmol) in aceticanhydride (50 mL) was added sodium acetate (NaOAc) (1.99 g, 24.3 mmol)and the mixture was heated at 120° C. for 3 hours. The mixture cooled toroom temperature and filtered through Celite. The filter cake was washedwith Et₂O (5×50 mL) and the mother liquor was concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography (Isco CombiFlash Rf unit, 120 g Redisep column, 30% EtOAcin hexanes) to give (3aR,6aS)-tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2 (1H)-carboxylate (5) as a whitefoam (2.17 g, 40%): ¹H NMR (500 MHz, CDCl₃) δ 3.69 (m, 2H), 3.22 (m,2H), 2.91 (m, 2H), 2.50 (m, 2H), 2.17 (m, 2H), 1.46 (s, 9H).

Step E: To a −78° C. cooled solution of (3aR,6aS)-tert-butyl5-oxohexahydrocyclopenta(c)pyrrole-2(1H)-carboxylate (5, 22.35 g, 99.2mmol) in THF (500 mL) was slowly added a solution of lithiumbis(trimethylsilyl)amide (LiHMDS) in THF (1.0 M, 129 mL). The mixturecontinued to stir a −78° C. for 30 minutes, then a solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methane-sulfonamide(49.65 g, 139 mmol) in THE (150 mL) was slowly added. The mixturestirred for an additional 1 hour at −78° C. and was then allowed to stirat room temperature for 2 hours. The mixture was concentrated underreduced pressure and the residue was purified by flash columnchromatography (Isco CombiPlash Rf unit, 330 g Redisep column, 0% to 50%EtOAc in hexanes) to give (3aS,6aS)-tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydro-cyclopenta[c]pyrrole-2(1H)-carboxylate(6) as a clear, viscous oil (1.56 g, quantitative): ¹H NMR (500 MHz,CDCl₃) δ 5.58 (s, 1H), 3.62 (m, 1H), 3.53 (m, 1H), 3.46 (m, 2H), 3.19(m, 1H), 2.95 (m, 2H), 2.46 (m, 1H), 1.47 (s, 9H).

Step F: To an N₂ degassed mixture of (3aS,6aS)-tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(6, 14.79 g, 41.4 mmol), 2-trifluoromethylphenylboronic acid (19.70 g,104 mmol), and a 2 M aqueous solution of Na₂CO₃ (250 mL) in DME (500 mL)was added Pd(PPh₂)₄ (4.80 g, 4.16 mmol). The mixture was heated at 80°C. for 6 hours, then cooled to room temperature and diluted with H₂O(500 mL). The aqueous mixture was extracted with EtOAc (2×200 mL) andthe combined organic extracts were washed with H₂O (200 mL), brine (200mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography (IscoCombiFlash Rf unit, 330 g Redisep column, 0% to 10% EtOAc in hexanes) togive (3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(7) as a clear, viscous oil (13.70 g, 94%): ¹H NMR (500 MHz, CDCl₂) δ7.65 (m, 1H), 7.47 (m, 2H), 7.25 (m, 1H), 5.58 (s, 1H), 3.85-3.42 (m,4H), 3.23 (m, 1H), 2.98 (m, 2H), 2.49 (m, 1H), 1.47 (s, 9H).

Step G: A mixture of (3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(7, 8.63 g, 24.4 mmol) and 10% Pd/C (1.57 g, wet, 10% w/w) in CH₃OH (50mL) was subjected to an atmosphere of H₂ gas (40 psi) using a ParrShaker apparatus for 16 hours at room temperature. The mixture wasfiltered through Celite and the filtrate was concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 30%EtOAc in hexanes) to give (3aR,5R,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (8) as a clear, viscousoil (0.91 g, 85%): ¹H NMR (500 MHz, CDCl₃) δ 7.69 (m, 1H), 7.51 (m, 2H),7.25 (m, 1H), 3.49 (m, 5H), 2.75 (m, 2H), 2.92 (m, 2H), 1.52 (m, 2H),1.48 (s, 9H).

Step H: To a 0° C. cooled solution of (3aR,5R,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta(c)pyrrole-2(1H)-carboxylate(8, 7.94 g, 22.3 mmol) in CH₂Cl₂ (60 mL) was added a 2 M HCl solution inEt₂O (60 mL), and the mixture was allowed to stir at room temperaturefor 24 hours. The mixture was diluted with Et₂O (200 mL) and theprecipitated product was filtered to give(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (9) as a white solid (5.90 g, 91%): ¹H NMR (500 MHz,CDCl₃) δ 10.17 (bs, 1H), 8.06 (m, 1H), 7.59 (m, 1H), 7.53 (m, 1H), 7.27(m, 1H), 3.42 (m, 2H), 3.38 (m, 3H), 3.01 (m, 2H), 2.36 (m, 2H), 1.96(m, 2H); MS (ESI+) m/z 256 [M+H]⁺.

Preparation of (3aR,5S,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrroleidine (10)

Step A: To a solution of (3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(7, 0.680 g, 1.92 mmol) in CH₂Cl₂ was added trifluoroacetic acid (TFA,1.5 mL). The mixture was stirred at room temperature for 16 hours andconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(25 mL) and washed with saturated aqueous NaHCO₃ solution (25 mL), brine(25 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was dissolved in CH₃OH (25 mL) and Pd/C was added(10% w/w, Degussa type E101 NE/W, 0.140 g). The mixture was subjected toan atmosphere of H₂ (50 psi) for 6 hours and was filtered throughCelite. The filtrated was concentrated under reduced pressure and theresulting residue was purified by reversed phase column chromatography(Isco C18 Reversed Phase Gold column, 10% to 30% CH₃CN in H₂O with 0.05%TFA). The resulting material was dissolved in CH₂Cl₂ and washed withsaturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydro-cyclopenta[c]pyrrole(10) as a white solid (0.070 g, 14%): ¹H NMR (300 MHz, CDCl₃) δ 7.61 (d,J=7.8 1H), 7.50 (m, 2H), 7.30-7.24 (m, 1H), 3.54-3.42 (m, 1H), 3.32-3.26(m, 2H), 2.81-2.68 (m, 2H), 2.51-2.46 (m, 2H), 1.84-1.76 (m, 4H); MS(ESI+) m/z 256 [M+H]⁺.

Preparation of(4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone Hydrochloride (12)

Step A: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (9, 0.292 g, 1.00 mmol),6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (0.268 g, 1.00 mol), and i-Pr₂NEt (0.52 mL, 3.00 mmol) in DMF (19mL) under an atmosphere of N₂ was added EDCI (0.230 g, 1.20 mmol) andHOBt (0.162 g, 1.20 mmol). The resulting solution was stirred at roomtemperature for 18 hours. The reaction mixture was diluted with H₂O (30mL). The resulting precipitate was collected by filtration and washedwith H₂O (50 mL) to provide tert-butyl3-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(11) as an off-white solid (390 mg, 77%): ¹H NMR (300 MHz, DMSO-d₆) δ12.99 (s, 1H), 7.72-7.57 (m, 3H), 7.43-7.34 (m, 1H), 4.54-4.45 (m, 2H),4.14-4.00 (m, 2H), 3.76-3.53 (m, 4H), 3.45-3.35 (m, 1H), 2.92-2.63 (m,4H), 2.30-2.14 (m, 2H), 1.64-1.47 (m, 2H), 1.42 (s, 9H); MS (ESI+) m/z505 [M+H]⁺.

Step B: To a suspension of tert-butyl3-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(11. 0.385 g, 0.763 mmol) in a 1:1 CH₂CH₃/CH₃OH (4.6 mL) was added a 2 NHCl solution in Et₂O (4.6 mL) and the resulting solution was stirred atroom temperature for 18 h. The mixture was diluted with Et₂O (30 mL) andthe solids obtained by filtration. The solids were washed with Et₂O (30mL) and dried to provide(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride(12) as an off-white solid (320 mg, 95%): ¹H NMR (300 MHz, DMSO-d₆) δ13.29 (br s, 1H), 9.22-9.11 (m, 2H), 7.71-7.58 (m, 3H), 7.43-7.34 (m,1H), 4.29-4.21 (m, 2H), 4.11-4.04 (m, 2H), 3.76-3.56 (m, 2H), 3.44-3.30(m, 3H), 2.99-2.70 (m, 4H), 2.31-2.14 (m, 2H), 1.65-1.46 (m, 2H); MS(ESI+) m/z 405 [M+H]⁺.

Preparation of(4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone Hydrochloride (14)

Step A: To a solution of (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (9, 0.271 g, 0.928 mmol),5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (0.250 g, 0.928 mmol), and i-Pr₂NEt (0.49 mL, 2.78 mmol) in DMF (18mL) under an atmosphere of N₂ was added EDCI (0.213 g, 1.11 mmol) andHOBt (0.150 g, 1.11 mmol). The resulting solution was stirred at roomtemperature for 18 h. The reaction mixture was diluted with H₂O (30 mL).The resulting precipitate was collected by filtration and washed withH₂O (50 mL). The solids were chromatographed over silica gel (0% to 5%CH₃OH in CH₂Cl₂ with 0.1% NH₄OH) to give tert-butyl3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (13) as a white solid (384 mg, 82%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.99 (br s, 1H), 7.71-7.58 (m, 3H), 7.43-7.33 (m, 1H),4.53-4.44 (m, 2H), 4.12-4.01 (m, 2H), 3.74-3.52 (m, 4H), 3.43-3.36 (m,1H), 2.94-2.61 (m, 4H), 2.31-2.13 (m, 2H), 1.64-1.46 (m, 2H), 1.42 (s,9H); MS (ESI+) m/z 505 [M+H]⁺.

Step B: To a suspension of tert-butyl3-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(13, 0.384 g, 0.761 mmol) in a 1:1 CH₂Cl₂/CH₃OH (4.6 mL) was added a 2 NHCl solution in Et₂O (4.6 mL) and the resulting solution was stirred atroom temperature for 18 hours. The mixture was diluted with Et₂O (50 mL)and the solids obtained by filtration. The solids were washed with Et₂O(30 mL) and dried to provide(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydro-cyclopenta[c]pyrrol-2(1H)-yl) methanone hydrochloride (14) asa white solid (325 mg, 97%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.29 (br s,1H), 9.21 (br s, 2H), 7.71-7.58 (m, 3H), 7.43-7.34 (m, 1H), 4.28-4.21(m, 2H), 4.12-4.05 (m, 2H), 3.76-3.51 (m, 2H), 3.44-3.30 (m, 3H),2.99-2.69 (m, 4H), 2.31-2.14 (m, 2H), 1.66-1.46 (m, 2H); MS (ESI+) m/z405 [M+H]⁺.

Preparation of(1,4,5,6-Tetrahydropyrrolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone Hydrochloride (16)

Step A: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (9, 0.300 g, 1.03 mmol),5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylicacid (0.260 g, 1.03 mmol), and i-Pr₂NEt (0.389 g, 3.09 mmol) in DMF (20mL) under an atmosphere of N₂ was added EDCI (0.236 g, 1.23 mmol) andHOBt (0.166 g, 1.23 mmol). The resulting solution was stirred at roomtemperature for 18 hours. The reaction mixture was diluted with H₂O (50mL) and the resulting solids collected by filtration. The obtainedsolids were chromatographed over silica gel (0% to 5% CH₃OH in CH₂Cl₂with 0.1% NH₄OH) to give tert-butyl3-((3aR,5Rr,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (15) as a white solid (349 mg, 69%): ¹H NMR (300 MHz.DMSO-d₆) δ 13.33-13.10 (m, 1H), 7.75-7.57 (m, 3H), 7.45-7.34 (m, 1H),4.56-4.31 (m, 4H), 4.13-4.01 (m, 1H), 3.79-3.53 (m, 3H), 3.44-3.34 (m,1H), 2.93-2.67 (m, 2H), 2.32-2.14 (m, 2H), 1.66-1.48 (m, 2H), 1.47-1.37(s, 9H); MS (ESI+) m/z 491 [M+H]⁺.

Step B: To a suspension of tert-butyl3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(15. 0.349 g, 0.711 mmol) in CH₂Cl₂ (3.0 mL) was added a 2 N HClsolution in Et₂O (3.0 mL) and the resulting solution was stirred at roomtemperature for 72 h. The mixture was diluted with Et₂O (30 mL) and thesolids obtained by filtration. The solids were washed with Et₂O (30 mL)and dried to provide(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl) methanone hydrochloride as ayellow-green foam (274 mg, 90%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (brs, 2H), 7.75-7.69 (m, 1H), 7.68-7.59 (m, 2H), 7.45-7.35 (m, 1H),4.46-4.27 (m, 4H), 3.95-3.81 (m, 1H), 3.78-3.52 (m, 3H), 3.46-3.29 (m,2H), 2.99-2.69 (m, 2H), 2.30-2.12 (m, 2H), 1.67-1.46 (m, 2H); MS (ESI+)m/z 391 [M+H]⁺.

EXAMPLE 1 2-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic Acid (17)

Step A: To a solution of(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole(0.640 g, 2.50 mmol) in CH₂Cl₂ (50 mL) was added methyl2-isocyanatobenzoate (0.442 g, 2.50 mmol) and the mixture stirred atroom temperature for 16 hours. The mixture was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 30%EtOAc in hexanes) to give methyl2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate as a white solid(0.700 g, 64%): MS (ESI+) m/z 433 [M+H]J.

Step B: To a solution of methyl2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate(0.700 g, 1.61 mol) in CH₃OH (20 mL) and THF (20 mL) was added aqueous 2N NaOH (10 mL). The mixture was stirred for 16 hours and concentratedunder reduced pressure. The residue was diluted with H₂O (25 mL), andacidified with 2 N HCl to pH 5 and the resulting precipitate wasfiltered to give2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoicacid as a white solid (0.668 g, 98%): mp 95-100° C.; ¹H NMR (500 MHz,DMSO-d) δ%): mp 157-161° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 13.46 (br s,1H), 10.79 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.96 (dd, J=8.0, 1.5 Hz,1H), 7.77-7.01 (m, 5H), 6.99 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.38 (m,3H), 2.86 (br s, 2H), 2.27-2.22 (m, 2H), 1.66-1.59 (m, 2K); MS (ESI+)m/z 419 [M+H]⁺.

EXAMPLE 2(1H-1,2,4-Triazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (18)

Step A: Following general procedure GP-A1,(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride and 1H-1,2,4-triazole-3-carboxylic acid were converted to(1H-1,2,4-triazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2 (1H)-yl)methanone as a white solid (0.071g, 52%): ¹H NMR (500 MHz, CDCl₃) δ 12.7.1 (bs, 1H), 8.12 (bs, 1H), 7.67(m, 1H), 7.49 (m, 2H), 7.26 (m, 1H), 4.43 (m, 2H), 3.93 (m, 2H), 3.53(m, 1H), 3.08-2.81 (m, 2H), 2.42 (m, 2H), 1.65 (m, 2H); ESI MS m/z 351[M+H]⁺.

EXAMPLE 3 (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (19)

Step A: To a solution of ethyl6-fluoro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.050 g, 0.239mmol) in THF (4 mL) was added a solution of LiOH.H₂O (0.030 g, 0.717mmol) in H₂ (3 mL). The mixture was stirred for 20 minutes, acidifiedwith 2 N HCl to pH 6, and concentrated under reduced pressure. To theresidue were added (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (0.070 g, 0.239 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.211 g, 0.478 mmol), i-Pr₂NEt (0.093 g, 0.717mmol), and DMF (4 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 mL)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 50% EtOAc in hexanes)and freeze dried to give(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a white solid (0.073g, 73%): mp 139-141° C.; ¹H NMR (300 MHz, CDC₃) δ 9.43 (m, 1H),7.92-7.87 (m, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.54-7.47 (m, 2H), 7.43-7.36(m, 1H), 7.28 (m, 1H), 4.53-4.41 (m, 2H), 4.00-3.85 (m, 2H), 3.63-3.53(m, 2H), 2.47-2.36 (m, 2H), 1.73-1.60 (m, 2H); MS (ESI+) m/z 419 [M+H]⁺.

EXAMPLE 4 (6,8-Dihydro-1,2,4-triazolo[3,4-c][1,4]oxazin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (20)

Step A: To a solution of ethyl6,8-dihydro-5R-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-carboxylate (0.070g, 0.355 mmol) in THF (3 mL) was added a solution of LiOH.H₂O (0.030 g,0.710 mmol) in H₂O (2 mL). The mixture was stirred for 20 minutes,acidified with 2 N HCl to pH 6 and concentrated under reduced pressure.To the residue were added(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (0.104 g, 0.355 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.314 g, 0.710 mmol), N,N-diisopropylethylamine(0.138 g, 1.07 mmol), and DMF (3 mL). The mixture was stirred at roomtemperature for 16 h and poured into H₂O. The mixture was extracted withEtOAc (30 mL) and the organic layer was washed with brine (2×30 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (0% to 100%EtOAc in hexanes) and freeze dried to give(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a white solid (0.052 g, 36%): mp 161-162° C.; ¹H NMR (300MHz, CDCl₃) δ 7.61 (d, J=7.8 Hz, 1H), 7.51 (m, 2H), 7.31-7.25 (m, 1H),5.03 (s, 2H), 4.54-4.47 (m, 2H), 4.38-4.27 (m, 2H), 4.08-4.00 (m, 2H),3.91-3.74 (m, 2H), 3.62-3.50 (m, 1H), 3.01-2.80 (m, 2H), 2.44-2.32 (m,2H), 1.69-1.56 (m, 4H); MS (ESI+) m/z 407 [M+H]4.

EXAMPLE 5 (6-Methoxy-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (21)

Step A: To a solution of ethyl6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.016 g, 0.316mol) in THF (5 mL) was added a solution of LiOH.H₂O (0.040 g, 0.948mmol) in H₂O (3 mL). The mixture was stirred for 20 minutes, acidifiedwith 2 N HCl to pH 6 and concentrated under reduced pressure. To theresidue were added(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (0.092 g, 0.316 mol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.280 g, 0.632 mmol), i-Pr₂NEt (0.123 g, 0.948mmol), and DMF (3 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 mL)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 50% EtOAc in hexanes)and freeze dried to give(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas an off-white solid (0.098 g, 78%): mp 147-152° C.; ¹H NMR (300 MHz,CDCl₃) δ 9.00 (m,1H) 7.78 (dd, J=9.9, 0.6 Hz, 1H), 7.63-7.47 (m, 3H),7.30-7.21 (3H), 4.54-4.42 (m, 2H), 4.00-3.85 (m, 5H), 3.66-3.53 (m, 1H),3.04-2.87 (m, 2H), 2.46-2.36 (m, 2H), 1.74-1.61 (m, 2H); MS (ESI+) m/z431 [M+H]⁺.

EXAMPLE 6 (6-Chloro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(22)

Step A: To a solution of ethyl6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.058 g, 0.257mmol) in THF (4 mL) was added a solution of LiOH.H₂O (0.032 g, 0.771mmol) in H₂O (2 mL). The mixture was stirred for 30 minutes, acidifiedwith 2 N HCl to pH 6 and concentrated under reduced pressure. To theresidue were added(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (0.075 g, 0.257 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.227 g, 0.514 mmol), i-Pr₂NEt (0.100 g, 0.771mmol), and DMF (2 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 mL)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 40% EtOAc in hexanes)and freeze dried to give(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (0.042 g, 37%): mp 147-150° C.; ¹H NMR (500 MHz, CDCl₃)δ 9.4 (m, 1H), 7.84 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.53-7.48 (m, 2H),7.41 (dd, J=10.0, 2.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 4.50-4.41 (m,2H), 3.99-3.86 (m, 2H), 3.63-3.55 (m, 1H), 3.04-2.87 (m, 2H), 2.44-2.37(m, 2H), 1.70-1.62 (m, 2H); MS (ESI+) m/z 435 [M+H]⁺.

EXAMPLE 7 (6-(Trifluoromethyl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (23)

Step A: To a solution of ethyl6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.072g, 0.278 mmol) in THF (3 mL) was added a solution of LiOH.H₂O (0.035 g,0.834 mmol) in H₂O (1 mL). The mixture was stirred for 30 minutes,acidified with 2 N HCl to pH 6 and concentrated under reduced pressure.To the residue were added (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (0.081 g, 0.278 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.246 g, 0.556 mmol), i-Pr₂NEt (0.108 g, 0.834mmol), and DMF (2 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 ms)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 40% EtOAc in hexanes)and freeze dried to give(6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (0.087 g, 66%): mp 154-156° C.; ¹H NMR (300 MHz,CDCl₃₂) δ 9.88 (m, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.63-7.49 (m, 4H), 7.27(m, 1H), 4.53-4.41 (m, 2H), 4.02-3.86 (m, 2H), 3.65-3.50 (m, 1H),3.06-2.89 (m, 2H), 2.48-2.36 (m, 2H), 1.72-1.61 (m, 2H); MS (ESI+) m/z469 [M+H]⁺.

EXAMPLE 8 (6-Ethoxy-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (24)

Step A: To a solution of ethyl6-ethoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.072 g, 0.306mmol) in THF (3 mL) was added a solution of LiOH.H₂O (0.038 g, 0.918mmol) in H₂O (1 mL). The mixture was stirred for 30 minutes, acidifiedwith 2 N HCl to pH 6 and concentrated under reduced pressure. To theresidue were added(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (0.089 g, 0.306 mol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.271 g, 0.612 mmol), i-Pr₂NEt (0.119 g, 0.918mmol), and DMF (3 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 mL)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 30% EtOAc in hexanes)and freeze dried to give(6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as an off-white solid(0.107 g, 78%): mp 110-112° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.98 (d, J=1.5Hz, 1H), 7.77 (m, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.54-7.47 (m, 2H),7.30-7.23 (m, 2H), 4.54-4.42 (m, 2H), 4.10 (q, J=6.9 Hz, 2H), 3.99-3.84(m, 2H), 3.65-3.52 (m, 1H), 3.06-2.84 (m, 2H), 2.46-2.35 (m, 2H),1.74-1.60 (m, 2H), 1.48 (t, J=6.9 Hz, 3H); MS (ESI+) m/z 445 [M+H]⁺.

EXAMPLE 9 2-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic Acid (25)

Step A: To a solution of(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole(10, 0.030 g, 0.118 mmol) in CH₂Cl₂ (2 mL) was added methyl2-isocyanatobenzoate (0.021 g, 0.118 mmol). The mixture was stirred for2 hours and then chromatographed over silica gel (0% to 50% EtOAc inhexanes) to give methyl2-((3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydro-cyclopenta[c]pyrrole-2-carboxamido)benzoateas a white solid (0.052 g, 100%): ¹H NMR (300 MHz, CDCl₃) δ 10.53 (s,1H), 8.67 (m, 1H), 8.01 (dd, J=8.0, 1.6 Hz, 1H), 7.62-7.46 (m, 4H), 7.28(m, 18), 6.99-6.94 (m, 1H), 3.92 (m, 5H), 3.79-3.67 (m, 1H), 3.38-3.33(m, 2H), 3.07 (m, 2H), 2.11-1.93 (m, 4H); MS (ESI+) m/z 433 [M+H]⁺.

Step C: To a solution of methyl methyl2-((3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate (0.052 g, 0.120 mmol) in THF (3 mL) and methanol (1 mL) wasadded a solution of LiOH.H₂O (0.015 g, 0.360 mmol) in H2O (1 mL). Themixture was stirred for 6 hours, acidified to pH 2 with 2 N HCl andpoured into H₂O. The mixture was extracted with CH₂Cl₂ (30 mL) and theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was chromatographedover silica gel (0 to 10% CH₃OH in CH₂Cl₂) and freeze dried to give2-((3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid as a whitesolid (0.049 g, 98%): mp 172-174° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d,J=8.7 Hz, 1H), 8.07 (dd. J=8.1, 1.5 Hz, 1H), 7.62-7.45 (m, 4H), 7.28 (a,1H), 7.02-6.96 (m, 1H), 3.94-3.87 (m, 2H), 3.79-3.67 (m, 1H), 3.38 (dd,J=10.8, 4.8 Hz, 2H), 3.07 (m, 2H), 2.10-1.93 (m, 4H); MS (ESI+) m/z 419[M+H]⁺.

EXAMPLE 10 3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicAcid (26)

Step A: To a solution of ethyl6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.485 g, 1.80 mol)in THF (15 mL) was added a solution of LiOH.H₂O (0.076 g, 1.80 mol) inH₂O (5 mL). The mixture was stirred for 20 minutes, acidified with 2 NHCl to pH 6 and concentrated under reduced pressure. To the residue wereadded (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (0.525 g, 1.80 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (1.20 g, 2.7 mmol), i-Pr₂NEt (0.698 g, 5.40 mmol),and DMF (15 mL). The mixture was stirred at room temperature for 16hours and poured into H2O. The mixture was extracted with EtOAc (150 mL)and the organic layer was washed with brine (2×150 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 50% EtOAc in hexanes)to give(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a white solid (0.485g, 56%): ¹H NMR (300 MHz, CDCl₃) δ 9.65 (m, 1H), 7.98 (dd, J=9.6, 0.9Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.53-7.47 (m, 3H), 7.28 (m, 1H),4.51-4.39 (m, 2H), 4.00-3.85 (m, 2H), 3.64-3.52 (m, 1H), 3.07-2.84 (m,2H), 2.50-2.33 (m, 2H), 1.72-1.60 (m, 2H); MS (ESI+) m/z 479 [M+H]⁺.

Step B:(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (0.080 g, 0.167 mmol),molybdenum hexacarbonyl (0.066 g, 0.251 mmol), Pd(OAc)₂ (0.0037 g,0.0167 mmol), xantphos (0.014 g, 0.0251 mmol), CH₃OH (0.054 g, 1.67mmol), Cs₂CO₃ (109 g, 0.334 mmol), and 1,4-dioxane (2 mL) was heated at80° C. for 2 hours in a sealed vessel and then allowed to cool to roomtemperature. The mixture was chromatographed over silica gel (0% to 60%EtOAc in hexanes) to give methyl3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylateas a white solid (0.024 g, 31%): ¹H NMR (300 MHz, CDCl₃) δ 10.12 (s,1H), 8.00-7.87 (m, 2H), 7.63-7.47 (m, 3H), 7.28 (m, 1H), 4.52-4.21 (m,2H), 4.03-3.88 (m, 5H), 3.65-3.53 (m, 1H), 3.06-2.89 (m, 2H), 2.47-2.36(m, 2H), 1.73-1.61 (m, 2H); MS (ESI+) m/z 459 [M+H]⁺.

Step C: To a solution of3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate(0.024 g, 0.0523 mmol) in THF (2 mL) was added a solution of LiOH.H₂O(0.004 g, 0.105 mmol) in H₂O (1 mL). The mixture was stirred for 30minutes, acidified with 2 N HCl to ph 6, and purified by C-18 reversephase column chromatography (10% to 60% CH₃CN in H₂O) to give3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid as a white solid (0.020 g, 86%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.51(s, 1H), 7.98 (d, J=9.3 Hz, 1H), 7.80-7.74 (m, 2H), 7.66-7.61 (m, 2H),7.38 (t, J=7.5 Hz, 1H), 4.29-4.18 (m, 2H), 3.88-3.78 (m, 2H), 3.41 (m,1H), 2.97-2.82 (m, 2H), 2.32-2.19 (m, 2H), 1.71-1.66 (m, 2H); MS (ESI+)m/z 445 [M+H]⁺.

EXAMPLE 11 N-Methyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide(27)

Step A: A mixture of(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (0.066 g, 0.138 mmol),molybdenum hexacarbonyl (0.054 g, 0.207 mmol), Pd(OAc)₂ (0.0015 g,0.0007 mmol), xantphos (0.008 g, 0.0138 mmol), methylanine (0.040 g,0.414 mmol, 33% in ethanol), i-Pr₂NEt (0.054 g, 0.414 mmol), and1,4-dioxane (2 mL) was heated at 80° C. for 2 hours in a sealed vesseland allowed to cool to room temperature. The mixture was chromatographedover silica gel (0% to 10% CH₃OH in CH₂Cl₂) and further purified by C-18reverse phase column chromatography (10% to 60% CH₃CN in H₂O) to giveN-methyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamideas a white solid (0.034 g, 54%): mp 164-168° C.; ¹H NMR (300 Hz, CDCl₃)δ 9.83 (m, 1H), 7.91 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.53-7.47 (m, 2H),7.28 (m, 1H), 6.31 (br s, 1H), 4.48 (m, 2H), 4.00-3.85 (m, 2H),3.66-3.53 (m, 1H), 3.05 (d, J=4.9 Hz, 3H), 3.01-2.88 (m, 2H), 2.48-2.37(m, 2H), 1.73-1.62 (m, 2H); MS (ESI+) m/z 458 [M+H]⁺.

EXAMPLE 12N,N-Dimethyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide(28)

Step A: A mixture of6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(0.066 g, 0.138 mmol), molybdenum hexacarbonyl (0.054 g, 0.207 mmol),Pd(OAc)₂ (0.0015 g, 0.0007 mmol), xantphos (0.008 g, 0.0138 mmol),dimethylamine hydrochloride (0.056 g, 0.690 mmol), i-PraNEt (0.125 g,0.966 mmol), and 1,4-dioxane (2 mL) was heated at 80° C. for 2 hours ina sealed vessel and allowed to cool to room temperature. The mixture waschromatographed over silica gel (0% to 10% CH₃OH in CH₂Cl₂) and furtherpurified by C-18 reverse phase column chromatography (10% to 60% CH₃CNin H₂O) to giveN,N-dimethyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamideas a white solid (0.047 g, 72%): mp 83-87° C.; ¹H NMR (300 (Hz, CDCl₃) δ9.56 (m, 1H), 7.92 (dd, J=9.4, 1.0 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H),7.55-7.47 (m, 3H), 7.28 (m, 1H), 4.52-4.40 (m, 2H), 3.99-3.85 (m, 2H),3.64-3.52 (m, 1H), 3.14 (s, 6H), 3.07-2.84 (m, 2H), 2.47-2.36 (m, 2H),1.72-1.59 (m, 2H); MS (ESI+) m/z 472 [M+H]⁺.

EXAMPLE 131-Methyl-3-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-urea(29)

Step A: A mixture of 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (0.066 g, 0.138 mmol),Pd(OAc)₂ (0.003 g, 0.0138 mmol), xantphos (0.012 g, 0.0207 mmol),methylurea (0.020 g, 0.276 mol), Cs₂CO₃ (0.067 g, 0.207 mmol), and1,4-dioxane (2 mL) was heated at 110° C. for 6 hours and cooled to roomtemperature. The mixture was chromatographed over silica gel (0% to 10%CH₃OH in CH₂Cl₂) and further purified by C-18 reverse phase columnchromatography (10% to 60% CH₂CN in H₂O) to give1-methyl-3-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ureaas a white solid (0.010 g, 15%): sip 230-236° C.; ¹H NMR (300 MHz,CDCl₃) δ 9.48 (s, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.62-7.47 (m, 4H), 7.06(a, 1H), 5.09 (s, 1H), 4.41 (m, 2H), 3.97-3.83 (m, 2H), 3.57 (m, 1H),3.00-2.87 (m, 5H), 2.45-2.36 (m, 2H), 1.63 Cm, 2H); MS (ESI+) m/z 473[M+H]⁺.

EXAMPLE 141,1-Dimethyl-3-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-urea(30)

Step A: A mixture of6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(0.066 g, 0.138 mmol), Pd(OAc)₂ (0.003 g, 0.0138 mmol), xantphos (0.012g, 0.0207 mmol), N,N-dimethylurea (0.018 g, 0.207 mmol), Cs₂CO₃ (0.067g, 0.207 mmol), and 1,4-dioxane (2 mL) was heated at 100° C. for 6 hoursand cooled to room temperature. The mixture was chromatographed oversilica gel (0% to 10% CH₃OH in CH₂Cl₂) and further purified by C-18reverse phase column chromatography (10% to 60% CH₃CN in H₂O) to give1,1-dimethyl-3-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ureaas a white solid (0.023 g, 34%): mp 110-115° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.43 (m, 1H), 7.79 (m, 1H), 7.69-7.47 (m, 4H), 7.30-7.25 (m, 1H),4.48-4.37 (m, 2H), 3.97-3.83 (m, 2H), 3.63-3.51 (m, 1H), 3.06 (s, 6H),3.02-2.83 (m, 2H), 2.45-2.34 (m, 2H), 1.72-1.59 (m, 2H); MS (ESI+) m/z487 [M+H]⁺.

EXAMPLE 15 N-Methyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-sulfonamide(31)

Step A: A mixture of6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (0.090 g, 0.188 mmol),Pd(OAc)₂ (0.0042 g, 0.0188 mol), xantphos (0.016 g, 0.0282 mmol), benzylmercaptan (0.035 g, 0.282 mmol), i-Pr₂NEt (0.073 g, 0.564 mol), and1,4-dioxane (2 mL) was heated at 110° C. for 16 hours and cooled to roomtemperature. The mixture was chromatographed over silica gel (0% to 50%EtOAc in hexanes) to give(6-(benzylthio)-(1,2,4)triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl) methanone as a mixture withunreacted benzyl mercaptan (0.090 g in a ratio of 1:1.4): thick oil; MS(ESI+) m/z 523 [M+H]⁺.

Step B: The material obtained in Step A was dissolved in HOAc (3 mL) andH₂O (1 mL). N-Chlorosuccinimide (NCS, 0.040 g, 0.296 mmol) was added andthe mixture was stirred for 3 hours then concentrated under reducedpressure. The residue was partitioned between saturated aqueous Na₂CO₃(50 mL) and CH₂Cl₂ (50 mL). The organic layer was separated and washedwith brine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was chromatographed over silicagel (0% to 50% EtOAc in hexanes) to give3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonylchloride as a mixture with unreacted NCS (0.032 g): thick oil; ¹H NMR(300 MHz, CDCl₃) δ 10.28 (m, 1H), 8.08 (dd, J=9.7, 0.8 Hz, 1H), 7.89(dd, J=9.7, 1.9 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.53-7.47 (m, 2H), 7.29(m, 1H), 4.51-4.40 (m, 2H), 4.03-3.87 (m, 2H), 3.66-3.53 (m, 1H),3.10-2.86 (m, 2H), 2.49-2.37 (m, 2H), 1.72-1.60 (m, 2H); MS (ESI+) m/z499 [M+H]⁺.

Step C: The material obtained in Step B was dissolved in CH₂Cl₂ (1 mL)and cooled to 0° C. A mixture of methylamine (33% in EtOH, 0.018 g,0.192 mmol) and N,N-diisopropylethylamine (0.025 g, 0.192 mmol) inCH₂Cl₃ (1 mL) was added. The mixture was stirred at room temperature for2 hours and then concentrated under reduced pressure. The residue waschromatographed by C-18 reverse phase column chromatography (10% to 50%CH₃CN in H₂O) to giveN-methyl-3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamideas a white solid (6.0 mg, 6% over three steps): mp 148-152° C.; ¹H NMR(300 MHz, CDCl₃) 510.0 (m, 1H), 7.99 (dd, J=9.6, 0.8 Hz, 1H), 7.73 (dd,J=9.6, 1.7 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.54-7.47 (m, 2H), 7.28 (m,1H), 4.59 (q, J=5.2 Hz, 1H), 4.50-4.39 (m, 2H), 4.01-3.86 (m, 2H),3.65-3.53 (m, 1H), 3.08-2.86 (m, 2H), 2.81 (d, J=5.3 Hz, 3H), 2.48-2.36(m, 2H), 1.71-1.60 (m, 2H); MS (ESI+) m/z 494 [M+H]⁺.

EXAMPLE 16 3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile(32)

Step A: A mixture of6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(0.080 g, 0.167 mmol), ZnCN₂ (0.039 g, 0.335 mmol), Pd(PPh₃)₄ (0.019 g,0.0167 mol), and DMF (2 mL) was heated at 130° C. under microwaveirradiation for 30 minutes. After cooling to room temperature, themixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL).The organic extract was washed with brine (2×50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrileas a white solid (0.073 g, 100%): mp 60-65° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.98 (m, 1H), 7.99 (dd, J=9.5, 0.9 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H),7.53-7.47 (m, 3H), 7.28 (m, 1H), 4.51-4.40 (m, 2H), 4.02-3.86 (m, 2H),3.66-3.54 (m, 1H), 3.09-2.86 (m, 2H), 2.49-2.37 (m, 2H), 1.71-1.60 (m,2H); MS (ESI+) m/z 426 [M+H]⁺.

EXAMPLE 17 3-(3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-carboxamide(33)

Step A: To a solution of3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile(0.038 g, 0.0893 mmol) in THF (3 mL) was added a solution of LiOH.H₂O(0.007 g, 0.179 mmol) in H₂O (1 mL). The mixture was stirred for 20minutes, acidified with 2 N HCl to pH 6 and purified by C-18 reversephase column chromatography (10% to 60% CH₃CN in H₂O) to give3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamideas a white solid (0.031 g, 77%): mp 238-243° C.; 1H NMR (300 MHz,DMSO-d₆) δ 9.95 (s, 1H), 8.87 (br s, 2H), 7.95 (d, J=9.2 Hz, 1H),7.74-7.63 (m, 3H), 7.40 (t, J=7.6 Hz, 1H), 7.01 (d, J=9.1 Hz, 1H),4.01-3.94 (m, 2H), 3.82-3.68 (m, 3H), 3.45-3.31 (m, 1H), 2.85 (m, 2H),2.32-2.15 (m, 2H), 1.66-1.52 (m, 2H); MS (ESI+) m/z 444 [M+H]⁺.

EXAMPLE 18 (7-(Trifluoromethyl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(24)

Step A: To a solution of ethyl7-(trifluoromethyl)-(1,2,4)triazolo[4,3-a]pyridine-3-carboxylate (0.072g, 0.278 mmol) in THF (3 mL) was added a solution of LiOH.H₂O (0.035 g,0.834 mol) in H₂O (1 mL). The mixture was stirred for 20 minutes,acidified with 2 N HCl to pH 6 and concentrated under reduced pressure.To the residue were added(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (9, 0.081 g, 0.278 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.184 g, 0.417 mmol), i-Pr₂NEt (0.108 g, 0.834mmol), and DMF (2 mL). The mixture was stirred at room temperature for16 hours and poured into H₂O. The mixture was extracted with EtOAc (30mL) and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 40% EtOAc in hexanes)and freeze dried to give(7-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as an off-white solid(0.072 g, 55%): mp 130-132° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.98 (d, J=7.4Hz, 1H), 8.22 (m, 1H), 7.63-7.47 (m, 3H), 7.28 (m, 1H), 7.18 (dd, J=7.4,1.7 Hz, 1H), 4.53-4.41 (m, 2H), 4.02-3.86 (m, 2H), 3.66-3.54 (m, 1H),3.09-2.86 (m, 2H), 2.48-2.37 (m, 2H), 1.73-1.60 (m, 2H); MS (ESI+) m/z469 [M+H]⁺.

EXAMPLE 19 (7-Methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(35a)

Step A: To a solution of ethyl7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.067 g, 0.326mmol) in THF (3 mL) was added a solution of LiOH.H₂O (0.041 g, 0.978mmol) in H₂O (1 mL). The mixture was stirred for 20 minutes, acidifiedwith 2 N HCl to pH 6 and concentrated under reduced pressure. To theresidue were added (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (9, 0.095 g, 0.326 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.216 g, 0.489 mmol), i-Pr₂NEt (0.119 g, 0.978mmol), and DMF (2 mL). The mixture was stirred at room temperature for16 h and poured into H₂O. The mixture was extracted with EtOAc (30 mL)and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 70% EtOAc in hexanes)and freeze dried to give(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (0.103 g, 76%): mp 176-180° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.29 (d, J=7.2 Hz, 1H), 7.62-7.46 (m, 4H), 7.26 (m, 1H), 6.85 (dd,J=7.2, 1.5 Hz, 1H), 4.53-4.40 (m, 2H), 3.99-3.84 (m, 2H), 3.64-3.52 (m,1H), 3.06-2.83 (m, 2H), 2.48 (s, 3H), 2.46-2.35 (m, 2H), 1.73-1.60 (m,2H); MS (ESI+) m/z 415 [M+H]⁺.

EXAMPLE 20(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (35b)

Step A: To a solution of ethyl6-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.067 g, 0.326mmol) in THF (3 mL) is added a solution of LiOH.H₂O (0.041 g, 0.978mmol) in H₂O (1 mL). The mixture is stirred for 20 minutes, acidifiedwith 2 N HCl to pH 6 and concentrated under reduced pressure. To theresidue are added (3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride (9, 0.095 g, 0.326 mmol),benzotriazole-1-yl-oxy-tris-(dimethylaminuteso)-phosphoniumhexafluorophosphate (0.216 g, 0.489 mmol), i-Pr₂NEt (0.119 g, 0.978mmol), and DMF (2 mL). The mixture is stirred at room temperature for 16h and poured into H₂O. The mixture is extracted with EtOAc (30 mL) andthe organic layer was washed with brine (2×30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residueis chromatographed over silica gel (0% to 70% EtOAc in hexanes) and isfreeze dried to give(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid.

EXAMPLE 21Pyrimidin-2-yl((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(36)

Step A: Following general procedure GP-A2,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrolehydrochloride and pyrimidine-2-carboxylic acid were converted topyrimidin-2-yl((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (127 mg, 76%): mp 84-92° C.; ¹H NMR (300 MHz, DMSO-d) δ8.92 (d, J=8.5 Hz, 2H), 7.75-7.58 (m, 4H), 7.45-7.36 (m, 1H), 3.74-3.64(m, 2H), 3.55-3.46 (m, 1H), 3.42-3.29 (m, 1H), 3.28-3.21 (m, 1H),2.94-2.71 (m, 2H), 2.33-2.21 (m, 1H), 2.18-2.07 (m, 1H), 1.65-1.44 (m,2H); MS (ESI+) m/z 362 [M+H]⁺.

EXAMPLE 22Pyridazin-3-yl((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(37)

Step A: Following general procedure GP-A2,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride and pyridazine-3-carboxylic were converted topyridazin-3-yl((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a clear viscous oil(109 mg, 66%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (dd, J=5.0, 2.0 Hz, 1H),7.98 (dd, J=8.5, 1.5 Hz, 1H), 7.87-7.84 (m, 1H), 7.74 (d, J=8.0 Hz, 1H),7.67-7.62 (m, 2H), 7.42-7.37 (m, 1H), 3.84-3.78 (m, 2H), 3.74-3.69 (m,1H), 3.65-3.60 (m, 1H), 3.42-3.33 (m, 1H), 2.87-2.79 (m, 2H), 2.30-2.23(m, 1H), 2.19-2.12 (m, 1H), 1.66-1.52 (m, 2H); MS (ESI+) m/z 362 [M+H]⁺.

EXAMPLE 23 (Pyrazin-2-yl((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (38)

Step A: Following general procedure GP-A1,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride and pyrazine-2-carboxylic were converted topyrazin-2-yl((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a clear oil (53.1 mg, 64%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=1.5 Hz, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.70-8.69 (m, 1H), 7.73 (d, J=8.5Hz, 1H), 7.67-7.62 (m, 2H), 7.42-7.37 (m, 1H), 3.86-3.80 (m, 1H),3.78-3.72 (m, 1H), 3.71-3.62 (m, 2H), 3.42-3.32 (m, 1H), 2.87-2.77 (m,2H), 2.29-2.22 (m, 1H), 2.19-2.12 (m, 1H), 1.64-1.51 (m, 2H); MS (ESI+)m/z 362 [M+H]⁺.

EXAMPLE 24(6-Morpholinoimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl) methanone (39)

Step A: Following general procedure GP-A1,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrolehydrochloride and 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acidwere converted to(6-chloroimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (134 mg, 63%) as an off-white solid: 1H NMR (300 MHz, DMSO-d₆)δ 8.72 (d, J=0.6 Hz, 1H), 8.31 (dd, J=9.6, 0.6 Hz, 1H), 7.73-7.59 (m,3H), 7.47 (d, J=9.6 Hz, 1H), 7.42-7.35 (m, 1H), 4.19-4.14 (m, 2H),3.80-3.65 (m, 2H), 3.45-3.30 (m, 1H), 2.92-2.75 (m, 2H), 2.32-2.15 (m,2H), 1.67-1.49 (m, 2H); MS (ESI+) m/z 435 [M+H]⁺.

Step B: A mixture of(6-chloroimidazo[1,2-b]pyridazin-2-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(0.064 g, 0.147 mmol) and morpholine (3.0 mL) was heated at 120° C. for2 hours. The mixture cooled to room temperature and was concentratedunder reduced pressure. The resulting residue was chromatographed oversilica gel (0% to 3% CH₃OH in CH₂Cl₂ with 0.1% NH₄OH) to give a residuethat was chromatographed over silica gel (0% to 3% CH₃OH in CH₂Cl₂ with0.01% NH₄OH) to give(6-morpholinoimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas an off-white solid (26.4 mg, 37%): mp 218-223° C.; 1H NMR (500 MHz,DMSO-d₆) δ 8.23 (s, 1H), 7.94 (d, J=10 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),7.67-7.60 (m, 2H), 7.41-7.36 (m, 1H), 7.27 (d, J=10.5 Hz, 1H), 4.24-4.13(m, 2H), 3.76-3.62 (m, 6H), 3.50-3.46 (m, 4H), 3.44-3.34 (m, 1H),2.92-2.72 (m, 2H), 2.30-2.18 (m, 2H), 1.63-1.51 (m, 2H); MS (ESI+) m/z486 [M+H]⁺.

EXAMPLE 25(6-Methylimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(40)

Step A: To a solution of(6-chloroimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(0.050 g, 0.115 mmol) in THF (0.5 mL) and NMP (44 μL) under N,atmosphere. To this was added Fe(acac)₃ (0.004 g, 0.0115 mmol) and theresulting solution was cooled to 0° C. A 1.4 M solution of CH₃MgBr inTHF/toluene (0.12 mL, 0.173 mmol) was added dropwise. The solution waswarmed to room temperature. After 1.5 hours, an additional 1.4 Msolution of CH₃MgBr in THF/toluene (0.04 mL) was added. The reaction wasstirred for 20 minutes then carefully diluted with EtOAc (3 mL) and 1 NHCl was added. The mixture was basified with saturated NaHCO₃ andextracted with EtOAc (3×30 mL). The combined organic extracts wereconcentrated under reduced pressure. The resulting residue waschromatographed over silica gel (0% to 5% CH₃OH in CH₂Cl₂ with 0.1%NH₄OH) to give(6-methylimidazo[1,2-b]pyridazin-2-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a white solid (24.5 mg, 51%): mp 167-169° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.70 (d,J=8.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.41-7.36 (m, 1H), 7.22 (d, J=9.5 Hz,1H), 4.23-4.15 (m, 2H), 3.77-3.65 (m, 2H), 3.44-3.34 (m, 1H), 2.93-2.74(m, 2H), 2.54 (s, 3H), 2.30-2.18 (m, 2H), 1.64-1.51 (m, 2H); MS (ESI+)m/z 415 [M+H]⁺.

EXAMPLE 26(1H-Pyrazolo[3,4-b]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (41)

Step A: Following general procedure GP-A2,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrolehydrochloride and 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid wereconverted to(1H-pyrazolo[3,4-b]pyridin-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (49 mg, 51%): mp 218-220° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 14.13 (s, 1H), 8.59 (dd, J=4.5, 2.0 Hz, 1H), 8.55 (dd, J=8.0, 1.5 Hz,1H), 7.72 (d, J=8.0 Hz, 1H), 7.66-7.59 (m, 2H), 7.41-7.36 (m, 1H),7.34-7.31 (m, 1H), 4.22-4.11 (m, 2H), 3.85-3.78 (m, 1H), 3.76-3.70 (m,1H), 3.46-3.37 (m, 1H), 2.96-2.77 (m, 2H), 2.31-2.19 (m, 2H), 1.68-1.57(m, 2H); MS (ESI+) m/z 401 [M+H)].

EXAMPLE 27 1-(3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone(42)

Step A: Following general procedure GP-E,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride and acetyl chloride were converted to1-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanoneas a white solid (48 mg, 60%): mp 207-213° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 13.00-12.94 (m, 1H), 7.71-7.60 (m, 3H), 7.42-7.36 (m, 11H), 4.66-4.52(m, 2H), 4.12-3.99 (m, 2H), 3.76-3.85 (m, 4H), 3.44-3.34 (m, 1H),2.87-2.80 (m, 1H), 2.79-2.70 (m, 2H), 2.69-2.62 (m, 1H), 2.29-2.15 (m,2H), 2.11-2.04 (m, 3H), 1.62-1.48 (m, 2H); MS (ESI+) m/z 447 [M+H]⁺.

EXAMPLE 28(6-(Methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclo-penta[c]pyrrol-2 (1H)-yl)methanone (43)

Step A: Following general procedure GP-F,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrolehydrochloride and methanesulfonyl chloride were converted to(6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (78.6 mg, 89%): mp 212-215° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.04 (s, 1H), 7.70-7.59 (m, 3H), 7.41-7.36 (m, 1H),4.43-4.34 (m, 2H), 4.11-4.02 (m, 2H), 3.72-3.58 (m, 2H), 3.52-3.34 (m,3H), 2.93 (s, 3H), 2.88-2.71 (m, 4H), 2.37-2.17 (m, 2H), 1.61-1.50 (m,2H); MS (ESI+) m/z 483 [M+H]⁺.

EXAMPLE 29(6-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (44)

Step A: Following general procedure GP-G,(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride and formaldehyde were converted to(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as a white solid (88.2 mg, 55%): ¹H NMR (500 MHz, DMSO-d₆) δ12.80 (s, 1H), 7.69-7.60 (m, 3H), 7.42-7.36 (m, 1H), 4.09-3.97 (m, 2H),3.69-3.57 (m, 2H), 3.47 (s, 2H), 3.43-3.32 (m, 1H), 2.88-2.71 (m, 2H),2.70-2.66 (m, 2H), 2.64-2.57 (m, 2H), 2.36 (s, 3H), 2.28-2.16 (m, 2H),1.59-1.48 (m, 2H); MS (ESI+) m/z 419 [M+H]⁺.

EXAMPLE 30 1-(3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(45)

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanonehydrochloride and methanesulfonyl chloride were converted to1-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneas a white solid (77.2 mg, 86%): mp 215-219° C.; 1H NMR (500 MHz,DMSO-d₆) δ 13.04 (s, 1H), 7.71-7.60 (m, 3H), 7.41-7.36 (m, 1H),4.44-4.34 (m, 2H), 4.12-4.02 (m, 2H), 3.73-3.58 (m, 2H), 3.53-3.33 (m,3H), 2.93 (s, 3H), 2.88-2.71 (m, 4H), 2.30-2.17 (m, 2H), 1.62-1.49 (m,2H); MS (ESI+) m/z 483 [M+H]⁺.

EXAMPLE 31 1-(3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(46)

Step A: Following general procedure GP-B,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanonehydrochloride and acetyl chloride were converted to1-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanoneas a white solid (57.2 mg, 69%): mp 191-199° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.01-12.94 (s, 1H), 7.70-7.60 (m, 3H), 7.41-7.36 (m, 1H),4.66-4.51 (m, 2H), 4.12-3.99 (m, 2H), 3.75-3.58 (m, 4H), 3.44-3.33 (m,1H), 2.89-2.70 (m, 3H), 2.68-2.62 (m, 1H), 2.29-2.16 (m, 2H), 2.11-2.04(m, 3H), 1.62-1.47 (m, 2H); MS (ESI+) m/z 447 [M+H]⁺; HPLC>99% purity(Method I).

EXAMPLE 32(5-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone(47)

Step A: Following general procedure GP-J,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanonehydrochloride and formaldehyde were converted to(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanoneas a white solid (33 mg, 27%): mp 156-159° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 12.95 (s, 1H), 7.70-7.67 (m, 1H), 7.66-7.61 (m, 2H), 7.41-7.36 (m,1H), 4.12-3.48 (m, 8H), 3.42-3.33 (m, 1H), 2.89-2.69 (m, 2H), 2.28-2.14(m, 2H), 1.62-1.47 (m, 2H); MS (ESI+) m/z 405 [M+H]⁺.

EXAMPLE 33(5-(Methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2 (1H)-yl)methanone (48)

Step A: Following general procedure GP-I,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride and methanesulfonyl chloride wereconverted to(5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (49 mg, 62%) as a whitesolid: mp 202-205° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.41-13.18 (m, 1H),9.04 (m, 1H), 7.74-7.60 (m, 3H), 7.42-7.35 (m, 1H), 4.62-4.50 (m, 2H),4.46-4.41 (m, 2H), 4.14-4.03 (m, 1H), 3.82-3.55 (m, 3H), 3.44-3.33 (m,1H), 3.05-2.99 (m, 3H), 2.91-2.70 (m, 2H), 2.29-2.18 (m, 2H), 1.62-1.49(m, 2H); MS (ESI+) m/z 469 [M+H]⁺.

EXAMPLE 34 1-(3-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydro-cyclopenta[c]pyrrole-2-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)ethanone(49)

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride and acetyl chloride were converted to1-(3-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrole-2-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)ethanone as awhite solid (20 mg, 28%): 1H NMR (500 MHz, DMSO-d₆) δ 13.36-13,14 (m,1H), 7.74-7.58 (m, 3H), 7.43-7.35 (m, 1H), 4.78-4.70 (m, 1H), 4.65-4.60(m, 1H), 4.57-4.46 (m, 1H), 4.41-4.37 (m, 1H), 4.10-4.05 (m, 1H),3.80-3.57 (m, 3H), 3.43-3.33 (m, 1H), 2.92-2.71 (m, 2H), 2.28-2.18 (m,2H), 2.07-2.01 (m, 3H), 1.61-1.50 (m, 2H); MS (ESI+) m/z 433 [M+H]⁺.

EXAMPLE 35 4-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinic acid (50)

Step A: To a solution of triphosgene (0.148 g, 0.500 mmol) in CH₂Cl₂(3.0 mL) under N₂, cooled to −78° C., was slowly added pyridine (0.158g, 2.00 mmol) and the resulting solution was stirred at −78° C. for 10minutes. A solution of(3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (9, 0.292 g, 1.00 mmol) in CH₂Cl₂ (2.0 mL) was added andthe resulting solution was stirred at −78° C. for 30 minutes. Thesolution was warmed to room temperature and stirred for 2 h. Thereaction was diluted with 1 N HCl (8 mL) and extracted with CH₂Cl₂ (3×30mL). The combined organic extracts were washed with saturated NaHCO₃solution (40 mL) and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0% to 30% EtOAc in hexanes)to give(3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonyl chloride as a light yellow solid (170 mg, 53%): 1H NMR(300 MHz, DMSO-d₆) δ 7.81 (d, J=8.4 Hz, 1H), 7.69-7.60 (m, 2H),7.44-7.35 (m, 1H), 3.85-3.75 (m, 1H), 3.71-3.54 (m, 2H), 3.51-3.43 (m,1H), 3.42-3.36 (m, 1H), 2.91-2.75 (m, 2H), 2.25-2.12 (m, 2H), 1.70-1.55(m, 2H): MS (ESI+) m/z 318 [M+H]⁺.

Step B: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonyl chloride (0.170 g, 0.536 mmol) in THF (3.0 mL) was addedi-Pr₂NEt (0.064 g, 0.536 mmol) and methyl 4-aminonicotinate (0.081 g,0.536 mmol) and the resulting solution was heated at 68° C. for 4 hours.The reaction was diluted with H₂O (20 mL) and extracted with EtOAc (3×30mL). The combined organic extracts were concentrated under reducedpressure. The resulting residue was chromatographed over silica gel (0to 5% CH₃OH in CH₂Cl₂ with 0.1% NH₄OH) to give methyl4-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinate as a white solid(140 mg, 60%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (br s, 1H), 8.98 (d,J=0.3 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.79 (d,J 8.1 Hz, 1H), 7.68-7.59 (m, 2H), 7.43-7.35 (m, 1H), 3.91 (s, 3H),3.75-3.61 (m, 2H), 3.52-3.35 (m, 3H), 2.94-2.81 (m, 2H), 2.31-2.17 (m,2H), 1.72-1.56 (m, 2H); MS (ESI+) m/z 434 [M+H]⁺.

Step C: To a solution of methyl4-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinate (0.138 g, 0.311 mmol) in THF (6.2 mL) and CH₃OH (3.2 mL) wasadded a solution of LiOH.H₂O (0.130 g, 3.11 mmol) in H₂O (1.6 mL). Themixture stirred for 3 hours, then acidified to pH 4 with 2 N HCl, anddiluted with H₂O (50 mL). The resulting solids were collected byfiltration and dried to provide4-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinic acid as a light yellow solid (130 mg, >99%): mp 245-255° C.decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 14.43-12.71 (m, 1H), 8.92 (m, 1H),8.53 (d, J=6.5 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H),7.67-7.59 (m, 2H), 7.42-7.36 (m, 1H), 3.75-3.62 (m, 2H), 3.53-3.35 (m,3H), 2.93-2.79 (m, 2H), 2.28-2.20 (m, 2H), 1.67-1.58 (m, 2H); MS (ESI+)m/z 420 [M+H]⁺.

EXAMPLE 36 5-methoxy-2-((3aR,5R,6aS)-5-(2-(Trifluormethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid (51)

Step A: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonyl chloride (0.100 g, 0.315 mmol) in THF (1.8 mL) was addedi-Pr₂NEt (0.041 g, 0.315 mmol) and methyl 2-amino-5-methoxybenzoate(0.057 g, 0.315 mmol). The resulting solution was heated at 68° C. for18 h. The reaction was diluted with H₂O (30 mL) and extracted with EtOAc(4×30 mL). The combined organic extracts were concentrated under reducedpressure. The resulting residue was chromatographed over silica gel (0%to 100% EtOAc in hexanes) to give methyl5-methoxy-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoateas a white film (94.9 mg, 65%): 1H NMR (500 MHz, CDCl₃) δ 10.27 (s, 1H),8.59 (d, J=9.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.55-7.46 (m, 3H),7.30-7.26 (m, 1H), 7.13 (dd, J=9.5, 3.5 Hz, 1H), 3.92 (s, 3H), 3.81 (s,3H), 3.76-3.72 (m, 2H), 3.59-3.48 (m, 3H), 2.93-2.85 (m, 2H), 2.41-2.33(m, 2H), 1.68-1.60 (m, 2H); MS (ESI+) m/z 463 [M+H]⁺.

Step B: To a solution of methyl5-methoxy-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido) benzoate (0.092 g, 0.199mmol) in THF (3.9 mL) and CH₃OH (2.0 mL) was added a solution ofLiOH.H₂O (0.084 g, 1.99 mmol) in H₂O (1.0 mL). The mixture was stirredfor 2 hours, then acidified with 2 N HCl, and diluted with H₂O (50 mL).The resulting solids were collected by filtration to provide5-methoxy-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido) benzoic acid as a whitesolid (77.2 mg, 86%): mp 176-179° C. decomp.; 1H NMR (500 MHz, DMSO-d) δ13.56 (s, 1H), 10.42 (br s, 1H), 8.43 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.67-7.59 (m, 2H), 7.43 (d, J=3.0 Hz, 1H), 7.42-7.36 (m, 1H),7.18 (dd, J=9.5, 3.0 Hz, 1H), 3.75 (s, 3H), 3.65-3.58 (m, 2H), 3.46-3.36(m, 3H), 2.90-2.79 (m, 2H), 2.28-2.19 (m, 2H), 1.66-1.57 (m, 2H); MS(ESI+) m/z 449 [M+H]⁺.

EXAMPLE 37 5-Fluoro-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid (52)

Step A: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonylchloride (0.100 g, 0.315 mmol) in THF (1.8 mL) was added i-Pr₂NEt (0.041g, 0.315 mmol) and methyl 2-amino-5-fluorobenzoate (0.064 g, 0.378mmol). The resulting solution was heated at 68° C. for 5 h. The reactionwas diluted with H₂O (30 mL) and extracted with EtOAc (4×30 mL). Thecombined organic extracts were concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (0% to 10% EtOAcin hexanes) to give methyl5-fluoro-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoateas a light orange film (101 mg, crude): MS (ESI+) m/z 451 [M+H]⁺.

Step B: To a solution of methyl5-fluoro-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido) benzoate (0.101 g, 0.224mmol) in THF (4.4 mL) and CH3OH (2.3 mL) was added a solution ofLiOH.H₂O (0.094 g, 2.24 mmol) in H₂O (1.2 mL). The mixture stirred for18 hours, then acidified with 2 N HCl, diluted with H₂O (20 mL), andextracted with EtOAc (3×30 mL). The combined organic extracts wereconcentrated under reduced pressure. The resulting residue waschromatographed by reverse phase column (0% to 100% CH₃CN in H₂O).Followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 15micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) to provide5-fluoro-2-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoicacid as a white solid (11 mg, 12%): mp 176-180° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.83 (br s, 1H), 10.65 (br s, 1H), 8.57-8.51 (m, 1H), 7.75(d, J=8.5 Hz, 1H), 7.69-7.59 (m, 3H), 7.46-7.36 (m, 2H), 3.67-3.58 (m,2H), 3.47-3.36 (m, 3H), 2.90-2.81 (m, 2H), 2.28-2.20 (m, 2H), 1.68-1.58(m, 2H); MS (ESI+) m/z 437 [M+H]⁺.

EXAMPLE 38 5-Chloro-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid (53)

Step A: To a solution of methyl 2-amino-5-chlorobenzoate (0.0.58 g,0.315 mmol) in DMF (2.7 mL) cooled to −10° C. under N₂ was added NaH(60% in mineral oil, 0.019 g, 0.473 mmol) and the resulting solution wasstirred at −10° C. for 20 minutes. A solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonylchloride (0.100 g, 0.315 mmol) in DMF (0.55 mL) was added and thereaction allowed to warm to room temperature and was stirred for 2.5 h.The reaction was carefully diluted with H₂O (30 mL), made acidic to pH 2with 2 N HCl, and extracted with EtOAc (4×30 mL). The combined organicextracts were washed with brine (4×30 mL) and concentrated under reducedpressure. The resulting residue was chromatographed over silica gel (0%10% CH₃OH in CH₂Cl₂ with 0.1% AcOH) followed by reverse phase columnchromatography (0% to 100% CH₃CN in H₂O). The obtained residue waspurified with preparative TLC (Analtech, 20×20 cm, 1000 microns, with 5%CH₃OH in CH₂Cl₂) to give5-chloro-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid as a whitesolid (21 mg, 23%): mp 188-193° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.92(br s, 1H), 10.85 (br s, 1H), 8.56 (d, J=9.5 Hz, 1H), 7.90 (s, 1H), 7.76(d, J=8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.42-7.35 (m, 1H), 3.67-3.58 (m,2H), 3.48-3.35 (m, 3H), 2.90-2.80 (m, 2H), 2.28-2.19 (m, 2H), 1.67-1.53(m, 2H); MS (ESI+) m/z 453 [M+H]⁺.

EXAMPLE 395-(Methylsulfonyl)-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid (54)

Step A: To a solution of methyl 2-amino-5(methylsulfonyl)benzoate (0.116g, 0.506 mmol) in DMF (4.4 mL) cooled to −10° C. under N₂ was added NaH(60% in mineral oil, 0.024 g, 0.606 mmol) and the resulting solution wasstirred at −10° C. for 30 minutes. A solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonylchloride (0.192 g, 0.606 mmol) in DMF (1.1 mL) was added and thereaction allowed to warm to room temperature and was stirred for 2hours. The reaction was carefully diluted with H₂O (20 mL), made acidicto pH 2 with 2 N HCl, and extracted with EtOAc (3×40 mL). The combinedorganic extracts were washed with brine (2×30 mL) and concentrated underreduced pressure. The resulting residue was chromatographed over silicagel (0% to 70% EtOAc in hexanes) followed by reverse phase columnchromatography (0% to 100% CH₃CN in H₂O) to give methyl5-(methylsulfonyl)-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate as a white film(76.2 mg, 29%): 1H NMR (300 MHz, CDCl₃) δ 10.91 (br s, 1H), 8.93 (d,J=9.3 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.01 (dd, J=9.0, 2.4 Hz, 1H),7.62 (d, J=7.8 Hz, 1H), 7.55-7.47 (m, 2H), 7.33-7.27 (m, 1H), 3.97 (s,3H), 3.86-3.73 (m, 2H), 3.64-3.47 (m, 3H), 3.06 (s, 3H), 2.98-2.86 (m,2H), 2.46-2.33 (m, 2H), 1.71-1.58 (m, 2H); MS (ESI+) m/z 511 [M+H]⁺.

Step B: To a solution of methyl5-(methylsulfonyl)-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate(0.075 g, 0.147 mmol) in THF (2.9 mL) and CH₃OH (1.5 mL) was added asolution of LiOH.H₂O (0.062 g, 1.47 mmol) in H₂O (0.74 mL). The mixturewas stirred for 5 hours, then acidified to pH 2 with 2 N HCl and dilutedwith H₂O (30 mL). The resulting precipitate was collected by filtrationand dried to provide5-(methylsulfonyl)-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic acid as a whitesolid (52 mg, 71%): mp 175-181° C.; 1H NMR (500 MHz, DMSO-d₆) δ 14.09(br s, 1H), 11.09 (br s, 1H), 8.77 (d, J=9.0 Hz, 1H), 8.42 (d, J=2.5 Hz,1H), 8.04 (dd, J=9.0, 2.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67-7.60 (m,2H), 7.42-7.37 (m, 1H), 3.72-3.64 (m, 2H), 3.52-3.46 (m, 2H), 3.45-3.32(m, 1H), 3.20 (s, 3H), 2.92-2.84 (m, 2H), 2.28-2.20 (m, 2H), 1.69-1.59(m, 2H); MS (ESI+) m/z 497 [M+H]+.

EXAMPLE 40 2-((3aR,5R,6aS)-5-(2-(Trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinic acid (55)

Step A: A solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonylchloride (0.300 g, 0.946 mmol) in 7 N NH₃ in CH₃OH (4.0 mL) was stirredfor 1 hour. The reaction was concentrated with Et₂O and dried to provide(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamideas a white solid (323 mg, >99%): MS (ESI+) m/z 299 [M+H]⁺.

Step B: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(0.100 g, 0.338 mmol), methyl 2-chloronicotinate (0.087 g, 0.507 mmol)and Cs₂CO₃ (0.134 g, 0.473 mmol) in deoxygenated toluene (4.0 mL) wasadded Pd(OAc)₂ (0.022 g, 0.0338 mmol) and racemic BINAP (0.042 g, 0.0676mmol) and the resulting solution was heated at reflux for 2 hours. Theresulting solution was cooled and filtered through Celite, which wasrinsed with EtOAc. The filtrate was washed with brine (3×30 mL) andconcentrated under reduced pressure. The resulting residue waschromatographed over silica gel (0% to 5% CH₃OH in CH₂Cl₂ with 0.01%NH₄OH) to give methyl2-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinateas a light orange film (46 mg, 31%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.41(br s, 1H), 8.69 (dd, J=4.8, 1.8 Hz, 1H), 8.32 (dd, J=7.8, 1.8 Hz, 1H),7.61 (d, J=7.8 Hz, 1H), 7.57-7.47 (m, 2H), 7.31-7.27 (m, 1H), 7.00 (dd,J=7.8, 4.8 Hz, 1H), 3.95 (s, 3H), 3.84-3.74 (m, 2H), 3.68-3.60 (m, 2H),3.58-3.43 (m, 1H), 2.95-2.83 (m, 2H), 2.43-2.32 (m, 2H), 1.72-1.57 (m,2H); MS (ESI+) m/z 434 [M+H]⁺.

Step C: To a solution of methyl2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinate (0.039 g, 0.090 mmol) in THF (4.0 mL) and CH₃OH (1.9 mL) wasadded a solution of LiOH.H₂O (0.037 g, 0.900 mmol) in H₂O (1.1 mL). Themixture stirred for 3 hours, then neutralized with 2 N HC and extractedwith CH₂Cl₂ (4×20 mL). The combined organic extracts were concentratedunder reduced pressure and the resulting residue was chromatographed byreverse phase column chromatography (0% to 60% CH₃CN in H₂O) to give2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)nicotinic acid as a white solid (21 mg, 55%): mp 129-133° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 14.00 (br s, 1H), 8.45-8.30 (m, 2H), 7.76 (d, J=7.8Hz, 1H), 7.70-7.60 (m, 2H), 7.45-7.34 (m, 1H), 7.17-7.09 (m, 1H),3.69-3.58 (m, 2H), 3.56-3.46 (m, 2H), 3.45-3.16 (m, 1H), 2.94-2.76 (m,2H), 2.31-2.17 (m, 2H), 1.70-1.54 (m, 2H); MS (ESI+) m/z 420 [M+H]⁺.

EXAMPLE 412-((3aS,6aR)-5-(2-(Trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoicacid (56)

Step A: To a solution of (3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(7, 120 mg, 0.34 mmol) in CH₂Cl₂ (3 mL) was added a TFA (3 mL) and theresulting solution was stirred at room temperature for 3 hours. Thereaction was concentrated under reduced pressure to provide the TFA saltof(3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrroleas an off-white solid (146 mg, >99%): ¹H NMR (300 MHz, CDCl₃) δ 9.21 (brs, 1H), 8.18 (br s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.51-7.34 (m, 3H), 5.57(s, 1H), 3.82 (br s, 1H), 3.62-3.54 (m, 2H), 3.39-3.09 (m, 4H),2.62-2.56 (m, 1H).

Step B: A solution of(3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrroleTFA salt (159 mg, 0.43 mmol), methyl 2-isocyanatobenzoate (91 mg, 0.51mmol), and Et₃N (0.14 mL, 1.0 mmol) in CH₂Cl₂ (6 mL) stirred for 64hours at room temperature. After this time, the reaction was dilutedwith saturated aqueous NaHCO₃ (30 mL) and extracted with dichloromethane(3×10 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (0% to 100% EtOAcin hexanes) to give methyl2-((3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoateas an off-white solid (114 mg, 62%): 1H NMR (300 MHz, CDCl₃) δ 8.66 (dd,J=8.4, 0.9 Hz, 1H), 8.02-7.98 (m, 1H), 7.66-7.64 (m, 1H), 7.54-7.34 (m,4H), 6.99-6.93 (m, 1H), 5.67 (br s, 1H), 4.02-3.90 (m, 4H), 3.81-3.67(m, 3H), 3.37-3.31 (m, 1H), 3.16-2.97 (m, 2H), 2.58-2.53 (m, 1H).

Step C: To a stirring solution of methyl2-((3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate(114 mg, 0.26 mmol) in CH₃OH (4 mL) and THF (4 mL) was added a solutionof LiOH.H₂O (110 mg, 2.62 mmol) in H₂O (2 mL). The mixture stirred for 4hours at room temperature, was diluted with additional H₂O (10 mL), andacidified with 2 N HCl to pH 6. The resulting solids were collected byfiltration and dried under reduced pressure to provide2-((3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoicacid as a white solid (85 mg, 79%): mp 148-152° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.50 (br s, 1H), 10.74 (s, 1H), 8.50 (d, J=8.5 Hz, 1H),7.96-7.94 (m, 1H), 7.73-7.42 (m, 6H), 7.01-6.98 (m, 1H), 5.68 (s, 1H),3.83-3.79 (m, 1H), 3.64-3.55 (m, 3H), 3.31-2.96 (m, 3H), MS (ESI−) m/z415 [M−H]⁻.

EXAMPLE 42(1H-1,2,3-Triazol-4-yl)((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexaydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (57)

Step A: Following general procedure GP-A1,(3aR,6aS)-5-(2-(trifluoromethyl)phenyl) octahydrocyclopenta[c]pyrrolehydrochloride and 1H-1,2,3-triazole-5-carboxylic acid were converted to(1H-1,2,3-triazol-4-yl){(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2 (1H)-yl}methanone as a white solid (0.039g, 53%): mp 163-165° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 15.46 (br s, 1H),8.32 (br s, 1H), 7.73-7.60 (m, 3H), 7.41-7.36 (m, 1H), 4.04-4.02 (m,1H), 3.76-3.61 (m, 2H), 3.98-3.96 (m, 1H), 2.89-2.78 (m, 2H), 2.26-2.22(m, 2H), 1.64-1.53 (m, 2H); MS (ESI+) m/z 351 [M+H]⁺.

EXAMPLE 43 Methyl6-methyl-2-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate (58)

The above compound was prepared according to General Procedure GP-K1.

EXAMPLE 44 Preparation of6-Methyl-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylicAcid (59)

Step A: To a solution of(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrolehydrochloride (1, 1.0 g, 3.43 mmol) and Et₃N (1.43 mL, 10.29 mmol) inDMF (50 mL) was added a methyl 2-chloropyrimidine-4-carboxylate (0.641g, 3.43 mmol) and the resulting solution was stirred at 60° C. for 16hours. The reaction was diluted with H₂O (200 mL) and extracted withEtOAc (3×100 mL). The combined organic extracts were washed with H₂O(3×100 mL), brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue waschromatographed over silica gel (0% to 30% EtOAc in hexanes) to givemethyl6-methyl-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylateas an off-white solid (1.20 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 7.61 (m,1H), 7.58 (m, 2H), 7.23 (m, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 3.82 (m,4H), 3.59 (m, 1H), 2.92 (m, 2H), 2.44 (s, 3H), 2.40 (m, 2H), 1.69 (m,2H); MS (ESI+) m/z 406 [M+H]⁺.

Step B: A solution of6-methyl-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate(1.2 g, 2.95 mmol) and 2 N NaOH (20 mL) in a 1:1 mixture of CH₃OH/THF(40 mL) stirred at room temperature for 16 hours. The mixture wascarefully neutralized at 0° C. with 2 N HCl and extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (0% to 10% CH₃OHin CH₂Cl₂) to give6-methyl-2-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylicacid as an off-white solid (1.0 g, 86%): ¹H NMR (300 MHz, CDCl₃) (7.62(m, 1H), 7.53 (m, 2H), 7.27 (m, 2H), 7.13 (s, 1H), 3.84 (m, 4H), 3.83.56(m, 1H), 2.99 (m, 2H), 2.48 (s, 3H), 2.41 (m, 2H), 1.67 (m, 2H); MS(ESI+) m/z 392 [M+H]⁺.

EXAMPLE 45 5-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)pyridazine-4-carboxylic acid(60)

The above compound was prepared according to the method describedhereinabove for the synthesis of compound 50.

EXAMPLE 46 3-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)pyrazine-2-carboxylic acid(61)

The above compound was prepared according to the method describedhereinabove for the synthesis of compound 50.

EXAMPLE 47 RPB4 binding of Octahydrocyclopentapyrroles Compounds

Various compounds listed in Examples 1-46 (compounds 17-24 and 27-39 and41-59) were tested in two in vitro assays, RBP4 binding (SPA) andretinol-dependent RBP4-TTR interaction (HTRF) (FIG. 8-9). The compoundsbinded to RBP4 and/or antagonized retinol-dependent RBP4-TTRinteraction. This activity indicates that the compounds reduce thelevels of serum RBP4 and retinol.

EXAMPLE 48 RPB4 binding of Additional OctahydrocyclopentapyrrolesCompounds

An additional aspect of the invention provides analogs of the compoundsof Examples 1-46 that are active as RBP4 antagonists. The analogs ofExamples 1-46 described herein analogously bind to RBP4 and antagonizeretinol-dependent RBP4-TTR interaction.

Additional octahydrocyclopentapyrroles compounds, which are analogs ofthose described in Example 1-46, are tested in two in vitro assays, RBP4binding (SPA) and retinol-dependent RBP4-TTR interaction (HTRF). Thesecompounds bind to RBP4 and antagonize retinol-dependent RBP4-TTRinteraction. This activity indicates that the compounds reduce the levelof serum RBP4 and retinol.

EXAMPLE 49 Efficacy in a Mammalian Model

The effectiveness of the compounds listed in Example 1-46 are tested inwild-type and Abca4−/− mice. The Abca4−/− mouse model manifestsaccelerated accumulation of lipofuscin in the RPE and is considered apre-clinical efficacy model for a drug reducing lipofuscin accumulation.Compounds are orally dosed for 3 weeks at 30 mg/kg. There is a reductionin the serum RBP4 level in treated animals. The levels of A2E/isoA2E andother bisretinoids are reduced in treated mice. The levels of A2-DHP-PEand atRAL di-PE are also reduced.

The effectiveness of additional octahydrocyclopentapyrroles compounds,which are analogs of those described in Examples 1-46, are tested inwild-type and Abca4−/− mice. The Abca4−/− mouse model manifestsaccelerated accumulation of lipofuscin in the RPE and is considered apre-clinical efficacy model for a drug reducing lipofuscin accumulation.Compounds are orally dosed for 3 weeks at 30 mg/kg. There is s reductionin the serum RBP4 level in treated animals. The levels of A2E/isoA2E andother bisretinoids are reduced in treated mice. The levels of A2-DHP-PEand atRAL di-PE are also reduced.

EXAMPLE 50 Preparation of(3aR,6aS)-2-(2-(Trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrroleHydrochloride (64)

Step A: To a stirring mixture of (3aR,6aS)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (62, 200 mg, 0.94mmol), rac-BINAP (25 mg, 0.04 mmol), and NaOt-Bu (120 mg, 1.25 mmol) indegassed toluene (63) (2 mas was added a 1-bromo-2-trifluoromethylbenzene (0.20 mL, 1.47 mol) and Pd(OAc)₂ (4 mg, 0.018 mmol) and themixture was heated at reflux for 18 hours. The mixture was allowed tocool to room temperature and was diluted with H₂O (10 mL) and extractedwith EtOAc (3×10 mL). The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (Isco CombiFlash Companionunit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide(3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(63) as a light brown oil (247 mg, 74%): ¹H NMR (300 MHz, CDCl₃) δ7.61-7.58 (i, 1H), 7.46-7.41 (m, 1H), 7.17-7.14 (m, 1H), 7.07-7.02 (m,1H), 3.70-3.66 (m, 2H), 3.64-3.28 (m, 4H), 3.14-3.10 (m, 2H), 2.96-2.90(m, 2H), 1.47 (s, 9H); MS (ESI+) m/z 357 [M+H]⁺.

Step B: A solution of (3aR,6aS)-tert-butyl5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(63, 247 mg, 0.69 mmol) in 4 M HCl solution in 1,4-dioxane (2 mL) wasstirred at room temperature for 4 hours. The mixture was concentratedunder reduced pressure to provide(3aR,6aS)-2-(2-(trifluoromethyl)phenyl) octahydrocpyrrolo[3,4, c]pyrrolehydrochloride (64) as an off-white solid (193 mg, 95%): ¹H NMR (300 MHz,DMSO-d₆) δ 9.15 (br s, 2H), 7.68-7.54 (m, 3H), 7.30 (t, J=7.5 Hz, 1H),3.57-3.52 (m, 2H), 3.36 (br s, 1H), 3.01-2.95 (m, 6H), 2.81-2.78 (m,2H); MS (ESI+) m/z 257 [M+H]⁺.

EXAMPLE 51 Preparation of(6-Methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (65)

HTRF assay for antagonists of RBP4-TTR RBP4 SPA Binding interactionCompound IC₅₀ (μM) IC₅₀ (μM) 65 0.00168 0.0208

Step A: A mixture of(3aR,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocpyrrolo[3,4, c]pyrrolehydrochloride (64, 95 mg, 0.32 mmol), sodium6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (93 mg, 0.35 mmol),EDCI (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol), DIPEA (0.08 mL, 0.46mmol) and DMF (3 mL) was stirred at room temperature for 40 hours. Themixture was concentrated under reduced pressure and the residue wasdiluted with H₂O (10 mL). The aqueous mixture was extracted with EtOAc(3×10 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was chromatographed over silica gel (IscoCombiFlash Companion unit, 12 g Redisep column, 0% to 100% EtOAc inhexanes) to provide(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanoneas an off-white solid (23 mg, 15%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (brs, 1H), 8.00-7.97 (m, 1H), 7.46-7.53 (m, 3H), 7.37-7.34 (m, 1H), 7.13(t, J=7.5 Hz, 1H), 4.42-4.37 (m, 1H), 4.10-3.93 (m, 2H), 3.69-3.63 (m,1H), 3.37-3.34 (m, 1H), 3.18-3.11 (m, 5H); MS (ESI+) m/z 480 [M+H]⁺.

Step B: To a mixture of(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(23 mg, 0.05 mmol), iron(II)acetylacetonate (2 mg, 0.005 mmol), andN-methylpyrrolidine (0.044 mL) in THF (0.5 mL) was added methylmagnesiumbromide (0.05 mL of a 1.4 M solution in THE) drop wise over 10 minutesat 0° C. The reaction was allowed to warm to room temperature andstirred for 2 hours. The mixture was diluted with EtOAc (20 mL) andcarefully quenched via dropwise addition of 1 N HCl. The reaction wasmade basic with saturated aqueous NaHCO₃ and was extracted with EtOAc(3×10 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure and the resultingresidue was chromatographed over silica gel (Isco CombiFlash Companionunit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(65) as an off-white solid (10 mg, 48%): 1H NMR (300 MHz, DMSO-d) δ 8.96(br s, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.61-7.34 (m, 4H), 7.13 (t, J=7.5Hz, 1H), 4.44-4.37 (m, 1H), 4.09-3.93 (m, 2H), 3.69-3.63 (m, 1H),3.37-3.34 (m, 1H), 3.17-3.05 (m, 5H), 2.36 (s, 3H); MS (ESI+) m/z 416[M+H]⁺.

EXAMPLE 52 General Procedures for Preparing Methyl2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate II

Conditions: A) Et₃N, DMF

General Procedure (GP-A) for 2-aminopyrimidine Formation: A mixture ofamine I (1 equiv), desired methyl 2-chloropyrimidine-4-carboxylate (1equiv), and triethylamine (Et₃N) (3 equiv) in DMF (0.25 M) was stirredat 60° C. until the reaction was complete by TLC or LC-MS. The mixturewas diluted with H₂O and extracted with EtOAc. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby either normal phase silica gel column chromatography (typical eluentsincluded either a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂and a 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18reversed phase column chromatography (typical eluents included CH₃CN andH₂O) to afford the desired ester II. The product structure was verifiedby ¹H NMR and by mass analysis.

EXAMPLE 53 Methyl6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate(66)

HTRF assay for antagonists of RBP4 SPA RBP4-TTR Binding interactionCompound IC₅₀ (μM) IC₅₀ (μM) 66 0.0039 0.074

The above compound was prepared according to the methods describedhereinabove in Example 52.

EXAMPLE 54 General Procedures for Preparing2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylic AcidIII

Conditions: B) 2N NaOH, CHsOH, THF

General Procedure (GP-B) for Carboxylic Acid Formation: A mixture ofester II (1 equiv) and aqueous 2 N NaOH (3 equiv) in a 1:1 mixture ofTHF and CH₃OH (0.25 M) was stirred at room temperature until thereaction was complete by TLC or LC-MS. The mixture was neutralized with2 N HCl and extracted with CH₂Cl₂. The combined organic extracts werewashed with H₂O, brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resulting residue was purified by eithernormal phase silica gel column chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) or C-18 reversedphase column chromatography (typical eluents included CH₃CN and H₂O) toafford the desired acid III. The product structure was verified by ¹HNMR and by mass analysis.

EXAMPLE 55 Preparation of6-Methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylicAcid (67)

Step A: Following general procedure GP-A,(3aR,6aS)-2-(2-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride and methyl 2-chloropyrimidine-4-carboxylate were convertedto methyl 6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate as anoff-white solid (0.200 g, 86%): MS (ESI+) m/z 407 [M+H]⁺.

Step B: Following general procedure GP-B, methyl6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylatewas converted to6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylicacid as an off-white solid (0.180 g, 86%): ¹H NMR (300 MHz, DMSO-d₆) δ13.2 (bs, 1H), 7.61 (m, 2H), 7.53 (m, 1H), 7.12 (m, 1H), 6.99 (s, 1H),3.90 (m, 2H), 3.46 (m, 4H), 3.14 (m, 4H), 2.36 (s, 3H); MS (ESI+) m/z393 [M+H]⁺.

EXAMPLE 56 RPB4 binding of Octahydropyrrolopyrrole 66

Compound 65 and 66 were tested in two in vitro assays, RBP4 binding(SPA) and retinol-dependent RBP4-TTR interaction (HTRF). The compoundsbinded to RBP4 and antagonized retinol-dependent RBP4-TTR interaction.This activity indicates that the compounds reduce the levels of serumRBP4 and retinol. Additional octahydropyrrolopyrroles compoundsdisclosed herein have analogous activity to octahydropyrrolopyrroleCompounds 65 and 66.

Additional octahydropyrrolopyrroles compounds disclosed herein haveanalogous activity to octahydrocyclopentapyrrole Examples 1-46.

Additional octahydropyrrolopyrroles compounds, which are analogs ofthose described in Examples 51, 53 and 55 are tested in two in vitroassays, RBP4 binding (SPA) and retinol-dependent RBP4-TTR interaction(HTRF). These compounds bind to RBP4 and antagonize retinol-dependentRBP4-TTR interaction. This activity indicates that the compounds reducethe level of serum RBP4 and retinol.

The octahydropyrrolopyrroles of the present invention are tested in twoin vitro assays, RBP4 binding (SPA) and retinol-dependent RBP4-TTRinteraction (HTRF). The compounds bind to RBP4 and/or antagonizeretinol-dependent RBP4-TTR interaction. This activity indicates that thecompounds reduce the levels of serum RBP4 and retinol.

EXAMPLE 57 Efficacy in a Mammalian Model

The effectiveness of the octahydropyrrolopyrroles 66 and 67 are testedin wild-type and Abca4−/− mice. The Abca4−/− mouse model manifestsaccelerated accumulation of lipofuscin in the RPE and is considered apre-clinical efficacy model for a drug reducing lipofuscin accumulation.Compounds are orally dosed for 3 weeks at 30 mg/kg. There is a reductionin the serum RBP4 level in treated animals. The levels of A2E/isoA2E andother bisretinoids are reduced in treated mice. The levels of A2-DHP-PEand atRAL di-PE are also reduced.

The effectiveness of the octahydropyrrolopyrroles of the presentinvention are tested in wild-type and Abca4−/− mice. The Abca4−/− mousemodel manifests accelerated accumulation of lipofuscin in the RPE and isconsidered a pre-clinical efficacy model for a drug reducing lipofuscinaccumulation. Compounds are orally dosed for 3 weeks at 30 mg/kg. Thereis a reduction in the serum RBP4 level in treated animals. The levels ofA2E/isoA2E and other bisretinoids are reduced in treated mice. Thelevels of A2-DHP-PE and atRAL di-PE are also reduced.

Discussion

Age-related macular degeneration (AMD) is the leading cause of blindnessin developed countries. Its prevalence is higher than that ofAlzheimer's disease. There is no treatment for the most common dry formof AMD. Dry AMD is triggered by abnormalities in the retinal pigmentepithelium (RPE) that lies beneath the photoreceptor cells and providescritical metabolic support to these light-sensing cells. RPE dysfunctioninduces secondary degeneration of photoreceptors in the central part ofthe retina called the macula. Experimental data indicate that highlevels of lipofuscin induce degeneration of RPE and the adjacentphotoreceptors in atrophic AMD retinas. In addition to AMD, dramaticaccumulation of lipofuscin is the hallmark of Stargardt's disease(STGD), an inherited form of juvenile onset macular degeneration. Themajor cytotoxic component of RPE lipofuscin is a pyridinium bisretinoidA2E. A2E formation occurs in the retina in a non-enzymatic manner andcan be considered a by-product of a properly functioning visual cycle.Given the established cytotoxic affects of A2E on RPE andphotoreceptors, inhibition of A2E formation could lead to delay invisual loss in patients with dry AMD and STGD. It was suggested thatsmall molecule visual cycle inhibitors may reduce the formation of A2Ein the retina and prolong RPE and photoreceptor survival in patientswith dry AMD and STGD. Rates of the visual cycle and A2E production inthe retina depend on the influx of all-trans retinol from serum to theRPE. RPE retinol uptake depends on serum retinol concentrations.Pharmacological downregulation of serum retinol is a valid treatmentstrategy for dry AMD and STGD. Serum retinol is maintained incirculation as a tertiary complex with retinol-binding protein (RBP4)and transthyretin (TTR). Without interacting with TTR, the RBP4-retinolcomplex is rapidly cleared due to glomerular filtration. Retinol bindingto RBP4 is required for formation of the RBP4-TTR complex; apo-RBP4 doesnot interact with TTR. Importantly, the retinol-binding site on RBP4 issterically proximal to the interface mediating the RBP4-TTR interaction.Without wishing to be bound by any scientific theory, the data hereinshow that small molecule RBP4 antagonists displacing retinol from RBP4and disrupting the RBP4-TTR interaction will reduce serum retinolconcentration, inhibit retinol uptake into the retina and act asindirect visual cycle inhibitors reducing formation of cytotoxic A2E.

Serum RBP4 as a Drug Target for Pharmacological Inhibition of the VisualCycle

As rates of the visual cycle and A2E production in the retina depend onthe influx of all-trans retinol from serum to the RPE (FIG. 4), it hasbeen suggested that partial pharmacological down-regulation of serumretinol may represent a target area in dry AMD treatment (11). Serumretinol is bound to retinol-binding protein (RBP4) and maintained incirculation as a tertiary complex with RBP4 and transthyretin (TTR)(FIG. 5). Without interacting with TTR, the RBP4-retinol complex israpidly cleared from circulation due to glomerular filtration.Additionally, formation of the RBP4-TTR-retinol complex is required forreceptor-mediated all-trans retinol uptake from serum to the retina.

Without wishing to be bound by any scientific theory, visual cycleinhibitors may reduce the formation of toxic bisretinoids and prolongRPE and photoreceptor survival in dry AMD. Rates of the visual cycle andA2E production depend on the influx of all-trans retinol from serum tothe RPE. Formation of the tertiary retinol-binding protein 4(RBP4)-transthyretin (TTR)-retinol complex in serum is required forretinol uptake from circulation to the RPE. Retinol-binding site on RBP4is sterically proximal to the interface mediating the RBP4-TTRinteraction. RBP4 antagonists that compete with serum retinol forbinding to RBP4 while blocking the RBP4-TTR interaction would reduceserum retinol, slow down the visual cycle, and inhibit formation ofcytotoxic bisretinoids.

RBP4 represents an attractive drug target for indirect pharmacologicalinhibition of the visual cycle and A2E formation. The retinol-bindingsite on RBP4 is sterically proximal to the interface mediating theRBP4-TTR interaction. Retinol antagonists competing with serum retinolfor binding to RBP4 while blocking the RBP4-TTR interaction would reduceserum RBP4 and retinol levels which would lead to reduced uptake ofretinol to the retina. The outcome would be visual cycle inhibition withsubsequent reduction in the A2E synthesis.

A synthetic retinoid called fenretinide[N-(4-hydroxy-phenyl)retinamide,4HRP] (FIG. 6) previously considered as a cancer treatment (29) wasfound to bind to RBP4, displace all-trans retinol from RBP4 (13), anddisrupt the RBP4-TTR interaction (13,14).

Fenretinide was shown to reduce serum RBP4 and retinol (15), inhibitocular all-trans retinol uptake and slow down the visual cycle (11).Importantly, fenretinide administration reduced A2E production in ananimal model of excessive bisretinoid accumulation, Abca4−/− mice (11).Pre-clinical experiments with fenretinide validated RBP4 as a drugtarget for dry AMD. However, fenretinide is non-selective and toxic.Independent of its activity as an antagonist of retinol binding to RBP4,fenretinide is an extremely active inducer of apoptosis in many celltypes (16-19), including the retinal pigment epithelium cells (20). Ithas been suggested that fenretinide's adverse effects are mediated byits action as a ligand of a nuclear receptor RAR (21-24). Additionally,similar to other retinoids, fenretinide is reported to stimulateformation of hemangiosarcomas in mice. Moreover, fenretinide isteratogenic, which makes its use problematic in Stargardt diseasepatients of childbearing age.

As fenretinide's safety profile may be incompatible with long-termdosing in individuals with blinding but non-life threatening conditions,identification of new classes of RBP4 antagonists is of significantimportance. The compounds of the present invention displace retinol fromRBP4, disrupt retinol-induced RBP4-TTR interaction, and reduce serumREBP4 levels. The compounds of the present invention inhibit bisretinoidaccumulation in the Abca4−/−mouse model of excessive lipofuscinogenesiswhich indicates usefulness a treatment for dry AMD and Stargardtdisease.

The present invention relates to small molecules for treatment ofmacular degeneration and Stargardt Disease. Disclosed herein is theophthalmic use of the small molecule as non-retinoid RBP4 antagonists.The octahydropyrrolopyrroles of the present invention bind RBP4 in vitroand/or antagonize RBP4-TTR interaction in vitro at biologicallysignificant concentrations. Additional compounds described herein, whichare analogs of Example 53 analogously bind RBP4 in vitro and antagonizeRBP4-TTR interaction in vitro at biologically significantconcentrations. Additional compounds described herein, which are azaanalogs of Example 1-46 analogously bind RBP4 in vitro and antagonizeRBP4-TTR interaction in vitro at biologically significantconcentrations.

Currently, there is no FDA-approved treatment for dry AND or Stargardtdisease, which affects millions of patients. An over the counter, nonFDA-approved cocktail of antioxidant vitamins and zinc (AREDS formula)is claimed to be beneficial in a subset of dry AMD patients. There areno treatments for Stargardt disease. The present invention identifiednon-retinoid RBP4 antagonists that are useful for the treatment of dryAMD and other conditions characterized by excessive accumulation oflipofuscin. Without wishing to be bound by any scientific theory, asaccumulation of lipofuscin seems to be a direct cause of RPE andphotoreceoptor demise in AMD and STGD retina, the compounds describedherein are disease-modifying agents since they directly address the rootcause of these diseases. The present invention provides novel methods oftreatment that will preserve vision in AMD and Stargardt diseasepatients, and patients' suffereing from conditions characterized byexcessive accumulation of lipofuscin.

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What is claimed is:
 1. A compound of the structure:

wherein R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ orC₁-C₄ alkyl; A is absent or present, and when present is

B is substituted or unsubstituted heterobicycle of the structure:

wherein n is an integer from 0-2; α, β, χ, δ, ε, and ϕ are eachindependently absent or present, and when present each is a bond; Z₁ isS, O or N; Z₂ is S, O, N or N—R₇, wherein R₇ is H, C₁-C₁₀ alkyl, oroxetane; X is C or N; Y₁, Y₂, Y₃, and each occurrence of Y₄ are eachindependently CR₈, C(R₉)₂, N—R₁₀, O, N, SO₂, or C═O, wherein R₈ is H,halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀ alkyl), C(O)OH,C(O)O(C₁-C₁₀ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄ alkyl), C(O)—N(C₁-C₄alkyl)₂, NHC(O)—NH(C₁-C₁₀ alkyl), NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH (C₁-C₁₀alkyl), SO₂—N(C₁-C₁₀ alkyl)₂, CN, or CF₃; R₉ is H or C₁-C₁₀ alkyl; andR₁₀ is H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃, (C₁-C₁₀alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl), SO₂—(C₁-C₁₀alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀ alkyl)-halogen,C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₁₀ alkyl)-CF₃, C(O)—(C₁-C₁₀ alkyl)-OCH₃,C(O)—(C₁-C₁₀ alkyl)-halogen, C(O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄alkyl)₂, (C₁-C₁₀ alkyl)-C(O)OH, C(O)—NH₂ or oxetane, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1 ofthe structure:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2 of the structure:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein B has the structure

wherein n is an integer from 0-2; α, β, χ, δ, ε, and ϕ are eachindependently absent or present, and when present each is a bond; Z₁ isS, O or N; Z₂ is S, O, N or N—R₇, wherein R₇ is H, C₁-C₁₀ alkyl, oroxetane; X is C or N; Y₁, Y₂, Y₃, and each occurrence of Y₄ are eachindependently CR₈, C(R₉)₂, N—R₁₀, O, N, SO₂, or C═O, wherein R₈ is H,halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀ alkyl), C(O)OH,C(O)O(C₁-C₁₀ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄ alkyl), C(O)—N(C₁-C₄alkyl)₂, NHC(O)—NH(C₁-C₁₀ alkyl), NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH(C₁-C₁₀alkyl), SO₂—N(C₁-C₁₀ alkyl)₂, CN, or CF₃; R₉ is H or C₁-C₁₀ alkyl; R₁₀is H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃, (C₁-C₁₀alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl), SO₂—(C₁-C₁₀alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀ alkyl)-halogen,C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₁₀ alkyl)-CF₃, C(O)—(C₁-C₁₀ alkyl)-OCH₃,C(O)—(C₁-C₁₀ alkyl)-halogen, C (O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄alkyl)₂, (C₁-C₁₀ alkyl)-C(O)OH, C(O)—NH₂ or oxetane, and wherein when αis present, then Z₁ and Z₂ are N, X is N, β is present, and χ and δ areabsent, or when α is present, then Z₁ is O or S, Z₂ is N, X is C, χ ispresent, and β and δ are absent; when α is absent, then Z₁ is N, Z₂ isN—R₇, X is C, β and δ are present, and χ is absent, or when α is absent,then Z₁ is N, Z₂ is O or S, X is C, β and δ are present, and χ isabsent; when ε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃,and Y₄ are independently C—R₈ or N; and when ε and ϕ are each absent,then n=0, 1 or 2, each of Y₁, Y₂, Y₃, and each occurrence of Y₄ areindependently C(R₉)₂, N—R₁₀, O, or SO₂, or a pharmaceutically acceptablesalt thereof.
 5. The compound of claim 1 of the structure:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. The compound of claim 4, wherein B has thestructure:

wherein n is 0; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁ and Y₃ are each CH₂or C(CH₃)₂; and Y₂ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄ alkyl,C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-C(O)OH,C(O)—NH₂ or oxetane, or a pharmaceutically acceptable salt thereof. 8.The compound of claim 4, wherein B has the structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁, Y₂ and Y₄ are eachCH₂ or C(CH₃)₂; and Y₃ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-C(O)OH,C(O)—NH₂ or oxetane, or a pharmaceutically acceptable salt thereof. 9.The compound of claim 4, wherein B has the structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁, Y₃ and Y₄ are eachCH₂ or C(CH₃)₂; and Y₂ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-C(O)OH,C(O)—NH₂ or oxetane, or a pharmaceutically acceptable salt thereof. 10.The compound of claim 4, wherein B has the structure:

wherein n is 2; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁, Y₃ and eachoccurrence of Y₄ are each CH₂ or C(CH₃)₂; and Y₂ is O, SO₂, or N—R₁₀,wherein R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,(C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen,C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃,C(O)—(C₁-C₄ alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,(C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane, or a pharmaceuticallyacceptable salt thereof.
 11. The compound of claim 4, wherein B has thestructure:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim4 wherein B has the structure:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim4, wherein B has the structure:

wherein n is 1; Y₁ and Y₄ are each CH₂; and one of Y₂ or Y₃ is CH₂ andthe other of Y₂ or Y₃ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl)-C(O)OH, oroxetane, or a pharmaceutically acceptable salt thereof.
 14. The compoundof claim 4, wherein B has the structure:

wherein n is 1; Y₁ and Y₄ are each CH₂; and one of Y₂ or Y₃ is CH₂ andthe other of Y₂ or Y₃ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl)-C(O)OH, oroxetane, or a pharmaceutically acceptable salt thereof.
 15. The compoundof claim 1, wherein B has the structure:

wherein R₇ is H, CH₃, CH₂CH₃, CH (CH₃)₂, or

 and each R₁₀ is H or CH₃, or a pharmaceutically acceptable saltthereof.
 16. The compound of 4, wherein B has the structure:

wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and Y₁, Y₂, Y₃ and Y₄ are eachindependently CR₈ or N, wherein each R₈ is independently H, halogen,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN or CF₃, or B has thestructure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein R₈ isH, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH,C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN or CF₃, or apharmaceutically acceptable salt thereof.
 17. The compound of claim 4,wherein B has the structure:

wherein n is 1; Y₁ and Y₄ are each CH₂; and one of Y₂ or Y₃ is CH₂ andthe other of Y₂ or Y₃ is O, SO₂, or N—R₁₀, wherein R₁₀ is H, C₁-C₄alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄alkyl)-halogen, SO₂—(C₁-C₄ alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄alkyl)-OCH₃, SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-C(O)OH oroxetane, or B has the structure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein eachR₈ is independently H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄alkyl), CN, CF₃, C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃ orNHC(O)—N(CH₃)₂, or B has the structure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein eachR₈ is independently H, halogen, O—(C₁-C₄ alkyl), CN or CF₃, or apharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising the compound of claim 5 and a pharmaceuticallyacceptable carrier.